|
Inhibition of PI3Kdelta
|
None
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases.
Year : 2012
Volume : 55
Issue : 20
First Page : 8559
Last Page : 8581
Authors : Cushing TD, Metz DP, Whittington DA, McGee LR.
|
Inhibition of PI3Kdelta in B-cells by proliferation assay
|
None
|
6.1
nM
|
|
Journal : J. Med. Chem.
Title : PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases.
Year : 2012
Volume : 55
Issue : 20
First Page : 8559
Last Page : 8581
Authors : Cushing TD, Metz DP, Whittington DA, McGee LR.
|
Inhibition of PI3K p110gamma (unknown origin)
|
Homo sapiens
|
89.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.
Year : 2013
Volume : 56
Issue : 5
First Page : 1922
Last Page : 1939
Authors : Morales GA, Garlich JR, Su J, Peng X, Newblom J, Weber K, Durden DL.
Abstract : Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.
|
Inhibition of PI3K p110delta (unknown origin)
|
Homo sapiens
|
2.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.
Year : 2013
Volume : 56
Issue : 5
First Page : 1922
Last Page : 1939
Authors : Morales GA, Garlich JR, Su J, Peng X, Newblom J, Weber K, Durden DL.
Abstract : Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.
|
Inhibition of PI3K p110beta (unknown origin)
|
Homo sapiens
|
562.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.
Year : 2013
Volume : 56
Issue : 5
First Page : 1922
Last Page : 1939
Authors : Morales GA, Garlich JR, Su J, Peng X, Newblom J, Weber K, Durden DL.
Abstract : Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.
|
Inhibition of PI3K p110alpha (unknown origin)
|
Homo sapiens
|
820.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.
Year : 2013
Volume : 56
Issue : 5
First Page : 1922
Last Page : 1939
Authors : Morales GA, Garlich JR, Su J, Peng X, Newblom J, Weber K, Durden DL.
Abstract : Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.
|
Inhibition of PI3Kbeta (unknown origin)
|
Homo sapiens
|
565.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting phosphoinositide 3-kinases
Year : 2012
Volume : 3
Issue : 11
First Page : 1337
Last Page : 1355
Authors : Wu P, Hu Y
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
820.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting phosphoinositide 3-kinases
Year : 2012
Volume : 3
Issue : 11
First Page : 1337
Last Page : 1355
Authors : Wu P, Hu Y
|
Inhibition of PI3Kgamma (unknown origin)
|
Homo sapiens
|
89.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting phosphoinositide 3-kinases
Year : 2012
Volume : 3
Issue : 11
First Page : 1337
Last Page : 1355
Authors : Wu P, Hu Y
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
2.5
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting phosphoinositide 3-kinases
Year : 2012
Volume : 3
Issue : 11
First Page : 1337
Last Page : 1355
Authors : Wu P, Hu Y
|
Inhibition of human PI3KCdelta by non-radiometric ADP-Glo assay
|
Homo sapiens
|
25.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Class II but Not Second Class-Prospects for the Development of Class II PI3K Inhibitors.
Year : 2015
Volume : 6
Issue : 1
First Page : 3
Last Page : 6
Authors : Mountford SJ, Zheng Z, Sundaram K, Jennings IG, Hamilton JR, Thompson PE.
Abstract : The Class II PI3 kinases are emerging from the shadows of their Class I cousins. The data emerging from PIK3C2 genetic modification studies and from siRNA knockdown suggest important roles in physiology and pathology. With some well-studied Class I isoform inhibitors showing strong Class II activity and a wealth of crystallographic information available, the structural similarity of these isoforms to Class I provides both the opportunity and the challenge in design of selective pharmacological inhibitors.
|
Inhibition of PI3Kdelta (unknown origin) by biochemical Alphascreen assay
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR study of potent and selective PI3Kδ inhibitors.
Year : 2015
Volume : 25
Issue : 5
First Page : 1104
Last Page : 1109
Authors : Bui M, Hao X, Shin Y, Cardozo M, He X, Henne K, Suchomel J, McCarter J, McGee LR, San Miguel T, Medina JC, Mohn D, Tran T, Wannberg S, Wong J, Wong S, Zalameda L, Metz D, Cushing TD.
Abstract : 2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.
|
Inhibition of PI3Kgamma (unknown origin) by biochemical Alphascreen assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR study of potent and selective PI3Kδ inhibitors.
Year : 2015
Volume : 25
Issue : 5
First Page : 1104
Last Page : 1109
Authors : Bui M, Hao X, Shin Y, Cardozo M, He X, Henne K, Suchomel J, McCarter J, McGee LR, San Miguel T, Medina JC, Mohn D, Tran T, Wannberg S, Wong J, Wong S, Zalameda L, Metz D, Cushing TD.
Abstract : 2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.
|
Inhibition of PI3Kdelta (unknown origin) assessed as inhibition of AKT phosphorylation by cell-based HTRF assay
|
Homo sapiens
|
2.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR study of potent and selective PI3Kδ inhibitors.
Year : 2015
Volume : 25
Issue : 5
First Page : 1104
Last Page : 1109
Authors : Bui M, Hao X, Shin Y, Cardozo M, He X, Henne K, Suchomel J, McCarter J, McGee LR, San Miguel T, Medina JC, Mohn D, Tran T, Wannberg S, Wong J, Wong S, Zalameda L, Metz D, Cushing TD.
Abstract : 2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.
|
Biochemical Assays: Compounds of the invention were tested for inhibitory activity and potency against PI3Kδ.
|
Homo sapiens
|
9.0
nM
|
|
Title : 6-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)ethyl]-3H-quinazolin-4-one as an inhibitor of human phosphatidylinositol 3-kinase delta
Year : 2013
|
Biochemical Assay: Using the method described in Example 2, compounds of the invention were tested for inhibitory activity and potency against PI3Kdelta, and for selectivity for PI3Kdelta versus other Class I PI3K isozymes. In Table 1, IC50 values (uM) are given for PI3Kdelta (Delta), and may be calculated for the other isoforms using the ratios of IC50 values discussed below. To illustrate selectivity of the compounds, the ratios of the IC50 values of the compounds for PI3Kalpha, PI3Kbeta, and PI3Kgamma relative to PI3Kdelta are given, respectively, as Alpha/Delta Ratio, Beta/Delta Ratio, and Gamma/Delta Ratio.The initial selectivity assays were performed identically to the selectivity assay protocol in Example 2, except, using 100 uL Ecosint for radiolabel detection. Subsequent selectivity assays were done similarly using the same 3 substrate stocks except they contained 0.05 mCi/mL gamma [32P] ATP and 3 mM PIP2. Subsequent selectivity assays also used the same 3 enzyme stocks.
|
Homo sapiens
|
9.0
nM
|
|
Title : 5-fluoro-3-phenyl-2[1-(9H-purin-6-ylamino)propyl]-3H-quinazolin-4-one and 6-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)ethyl]-3H-quinazolin-4-one as inhibitors of human phosphatidylinositol 3-kinase delta
Year : 2015
|
Inhibition of human PI3K 110gamma by fluorescence-based immunoassay
|
Homo sapiens
|
92.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Inhibition of human PI3K p110alpha/p85alpha by fluorescence-based immunoassay
|
Homo sapiens
|
825.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Inhibition of human PI3Kdelta by fluorescence-based immunoassay
|
Homo sapiens
|
3.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Antiproliferative activity against human HeLa cells after 72 hrs by MTT assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay
|
Homo sapiens
|
780.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Antiproliferative activity against human HepG2 cells after 72 hrs by MTT assay
|
Homo sapiens
|
920.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Antiproliferative activity against human A549 cells after 72 hrs by MTT assay
|
Homo sapiens
|
330.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Inhibition of human PI3K p110beta/p85beta by fluorescence-based immunoassay
|
Homo sapiens
|
579.0
nM
|
|
Journal : MedChemComm
Title : Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3K
Year : 2015
Volume : 6
Issue : 11
First Page : 2029
Last Page : 2035
Authors : Sha S, Han H, Gao F, Liu T, Li Z, Xu C, Zhong W, Zhu H
|
Inhibition of human PI3Kdelta (R108 to Q1044 residues) expressed in mammalian expression system incubated for 60 mins by ADAPTA assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors.
Year : 2016
Volume : 7
Issue : 10
First Page : 908
Last Page : 912
Authors : Ferguson FM, Ni J, Zhang T, Tesar B, Sim T, Kim ND, Deng X, Brown JR, Zhao JJ, Gray NS.
Abstract : Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.
|
Inhibition of human PI3Kgamma (S144 to A1102 residues) expressed in mammalian expression system incubated for 60 mins by ADAPTA assay
|
Homo sapiens
|
64.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors.
Year : 2016
Volume : 7
Issue : 10
First Page : 908
Last Page : 912
Authors : Ferguson FM, Ni J, Zhang T, Tesar B, Sim T, Kim ND, Deng X, Brown JR, Zhao JJ, Gray NS.
Abstract : Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.
|
Inhibition of his-tagged human recombinant PIK3CD/PIK3R1 by Select-screen kinase inhibitor assay
|
Homo sapiens
|
25.0
nM
|
|
Journal : J Med Chem
Title : Class II Phosphoinositide 3-Kinases as Novel Drug Targets.
Year : 2017
Volume : 60
Issue : 1
First Page : 47
Last Page : 65
Authors : Falasca M, Hamilton JR, Selvadurai M, Sundaram K, Adamska A, Thompson PE.
Abstract : The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. Despite the vast knowledge around class I PI3Ks, the class II PI3Ks have been neglected, seemingly only due to the chronology of their discovery. Here we focus on the cellular functions of the three class II PI3K isoforms, PI3KC2α, PI3KC2β, and PI3KC2γ, in different cell systems and underline the emerging importance of these enzymes in different physiological and pathological contexts. We provide an overview on the current development of class II PI3 kinase inhibitors and outline the potential use for such inhibitors. The field is in its infancy as compared to their class I counterparts. Nevertheless, recent advances in understanding the roles of class II PI3 kinases in different pathological contexts is leading to an increased interest in the development of specific inhibitors that can provide potential novel pharmacological tools.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of FMLP/cytochalasin B-induced superoxide anion generation by measuring superoxide dismutase-inhibitable reduction of ferricytochrome c preincubated for 5 mins followed by FMLP/cytochalasin B-induction by spectrophotometric analysis
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Nat Prod
Title : Chemical Constituents of the Rhizomes of Bletilla formosana and Their Potential Anti-inflammatory Activity.
Year : 2016
Volume : 79
Issue : 8
First Page : 1911
Last Page : 1921
Authors : Lin CW, Hwang TL, Chen FA, Huang CH, Hung HY, Wu TS.
Abstract : Nine new phenanthrenes (1-9) and a new benzyl glycoside (10) together with 45 known compounds were isolated from the rhizomes of Bletilla formosana. The structures of 1-10 were elucidated primarily on the basis of their 1D and 2D NMR spectroscopic data. Most of the isolated compounds were evaluated for their anti-inflammatory activities. The results showed that IC50 values for the inhibition of superoxide anion generation and elastase release ranged from 0.2 to 6.5 μM and 0.3 to 5.7 μM, respectively. Structure-activity relationships of the isolated compounds were also investigated. The inhibitory potencies were determined as phenanthrenes > bibenzyls > biphenanthrenes.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced elastase release using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as elastase substrate preincubated for 5 mins followed by fMLP/CB-induction
|
Homo sapiens
|
300.0
nM
|
|
Journal : J Nat Prod
Title : Chemical Constituents of the Rhizomes of Bletilla formosana and Their Potential Anti-inflammatory Activity.
Year : 2016
Volume : 79
Issue : 8
First Page : 1911
Last Page : 1921
Authors : Lin CW, Hwang TL, Chen FA, Huang CH, Hung HY, Wu TS.
Abstract : Nine new phenanthrenes (1-9) and a new benzyl glycoside (10) together with 45 known compounds were isolated from the rhizomes of Bletilla formosana. The structures of 1-10 were elucidated primarily on the basis of their 1D and 2D NMR spectroscopic data. Most of the isolated compounds were evaluated for their anti-inflammatory activities. The results showed that IC50 values for the inhibition of superoxide anion generation and elastase release ranged from 0.2 to 6.5 μM and 0.3 to 5.7 μM, respectively. Structure-activity relationships of the isolated compounds were also investigated. The inhibitory potencies were determined as phenanthrenes > bibenzyls > biphenanthrenes.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced superoxide anion generation by measuring superoxide dismutase-inhibitable reduction of ferricytochrome c at 10 uM preincubated for 5 mins followed by fMLP/CB-induction measured after 10 mins
|
Homo sapiens
|
103.0
%
|
|
Journal : J Nat Prod
Title : Halogenated Sesquiterpenoids from the Red Alga Laurencia tristicha Collected in Taiwan.
Year : 2016
Volume : 79
Issue : 9
First Page : 2315
Last Page : 2323
Authors : Chen JY, Huang CY, Lin YS, Hwang TL, Wang WL, Chiou SF, Sheu JH.
Abstract : Chemical investigation of the red alga Laurencia tristicha led to the discovery of eight new halogenated chamigrane-type sesquiterpenoids (1-8) and one new bromocuparane-type sesquiterpene (9), along with nine known related metabolites (10-18). Their structures were elucidated on the basis of extensive spectroscopic analyses, and the absolute configurations of 1-8 were proposed by comparison to the biosynthetically related known compound 12. Cytotoxicity, antibacterial, and anti-inflammatory activities of these isolates were also investigated. The results showed that compound 11 exhibited good antibacterial activity against Serratia marcescens compared to the positive control ampicillin at a dosage of 100 μg/disk. Compound 17 showed strong inhibition toward elastase release generation at 10 μM.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced elastase release at 10 uM using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as elastase substrate preincubated for 5 mins followed by fMLP/CB-induction
|
Homo sapiens
|
100.0
%
|
|
Journal : J Nat Prod
Title : Halogenated Sesquiterpenoids from the Red Alga Laurencia tristicha Collected in Taiwan.
Year : 2016
Volume : 79
Issue : 9
First Page : 2315
Last Page : 2323
Authors : Chen JY, Huang CY, Lin YS, Hwang TL, Wang WL, Chiou SF, Sheu JH.
Abstract : Chemical investigation of the red alga Laurencia tristicha led to the discovery of eight new halogenated chamigrane-type sesquiterpenoids (1-8) and one new bromocuparane-type sesquiterpene (9), along with nine known related metabolites (10-18). Their structures were elucidated on the basis of extensive spectroscopic analyses, and the absolute configurations of 1-8 were proposed by comparison to the biosynthetically related known compound 12. Cytotoxicity, antibacterial, and anti-inflammatory activities of these isolates were also investigated. The results showed that compound 11 exhibited good antibacterial activity against Serratia marcescens compared to the positive control ampicillin at a dosage of 100 μg/disk. Compound 17 showed strong inhibition toward elastase release generation at 10 μM.
|
Biochemical Assay: Using the method described in US9149477, Example 2, compounds of the invention were tested for inhibitory activity and potency against PI3Kδ, and for selectivity for PI3Kδ versus other Class I PI3K isozymes. The initial selectivity assays were performed identically to the selectivity assay protocol in US9149477, Example 2, except using 100 μL Ecoscint for radiolabel detection. Subsequent selectivity assays were done similarly using the same 3× substrate stocks except they contained 0.05 mCi/mL γ[32P]ATP and 3 mM PIP2. Subsequent selectivity assays also used the same 3× enzyme stocks, except they now contained 3 nM of any given PI3K isoform.
|
Homo sapiens
|
9.0
nM
|
|
Title : 5-fluoro-3-phenyl-2-[1-(9h-purin-6-ylamino)propyl]-3h-quinazolin-4-one as an inhibitor of human phosphatidylinositol 3-kinase delta
Year : 2015
|
Inhibition of human full length PI3K p110delta/p85 alpha using PIP2/ATP as substrate after 30 mins by TR-FRET assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856.
Year : 2017
Volume : 60
Issue : 4
First Page : 1555
Last Page : 1567
Authors : Perreault S, Chandrasekhar J, Cui ZH, Evarts J, Hao J, Kaplan JA, Kashishian A, Keegan KS, Kenney T, Koditek D, Lad L, Lepist EI, McGrath ME, Patel L, Phillips B, Therrien J, Treiberg J, Yahiaoui A, Phillips G.
Abstract : Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
2.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.
Year : 2017
Volume : 60
Issue : 12
First Page : 5193
Last Page : 5208
Authors : Liu Q, Shi Q, Marcoux D, Batt DG, Cornelius L, Qin LY, Ruan Z, Neels J, Beaudoin-Bertrand M, Srivastava AS, Li L, Cherney RJ, Gong H, Watterson SH, Weigelt C, Gillooly KM, McIntyre KW, Xie JH, Obermeier MT, Fura A, Sleczka B, Stefanski K, Fancher RM, Padmanabhan S, Rp T, Kundu I, Rajareddy K, Smith R, Hennan JK, Xing D, Fan J, Levesque PC, Ruan Q, Pitt S, Zhang R, Pedicord D, Pan J, Yarde M, Lu H, Lippy J, Goldstine C, Skala S, Rampulla RA, Mathur A, Gupta A, Arunachalam PN, Sack JS, Muckelbauer JK, Cvijic ME, Salter-Cid LM, Bhide RS, Poss MA, Hynes J, Carter PH, Macor JE, Ruepp S, Schieven GL, Tino JA.
Abstract : PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
|
Inhibition of PI3Kgamma (unknown origin)
|
Homo sapiens
|
63.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.
Year : 2017
Volume : 60
Issue : 12
First Page : 5193
Last Page : 5208
Authors : Liu Q, Shi Q, Marcoux D, Batt DG, Cornelius L, Qin LY, Ruan Z, Neels J, Beaudoin-Bertrand M, Srivastava AS, Li L, Cherney RJ, Gong H, Watterson SH, Weigelt C, Gillooly KM, McIntyre KW, Xie JH, Obermeier MT, Fura A, Sleczka B, Stefanski K, Fancher RM, Padmanabhan S, Rp T, Kundu I, Rajareddy K, Smith R, Hennan JK, Xing D, Fan J, Levesque PC, Ruan Q, Pitt S, Zhang R, Pedicord D, Pan J, Yarde M, Lu H, Lippy J, Goldstine C, Skala S, Rampulla RA, Mathur A, Gupta A, Arunachalam PN, Sack JS, Muckelbauer JK, Cvijic ME, Salter-Cid LM, Bhide RS, Poss MA, Hynes J, Carter PH, Macor JE, Ruepp S, Schieven GL, Tino JA.
Abstract : PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
800.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.
Year : 2017
Volume : 60
Issue : 12
First Page : 5193
Last Page : 5208
Authors : Liu Q, Shi Q, Marcoux D, Batt DG, Cornelius L, Qin LY, Ruan Z, Neels J, Beaudoin-Bertrand M, Srivastava AS, Li L, Cherney RJ, Gong H, Watterson SH, Weigelt C, Gillooly KM, McIntyre KW, Xie JH, Obermeier MT, Fura A, Sleczka B, Stefanski K, Fancher RM, Padmanabhan S, Rp T, Kundu I, Rajareddy K, Smith R, Hennan JK, Xing D, Fan J, Levesque PC, Ruan Q, Pitt S, Zhang R, Pedicord D, Pan J, Yarde M, Lu H, Lippy J, Goldstine C, Skala S, Rampulla RA, Mathur A, Gupta A, Arunachalam PN, Sack JS, Muckelbauer JK, Cvijic ME, Salter-Cid LM, Bhide RS, Poss MA, Hynes J, Carter PH, Macor JE, Ruepp S, Schieven GL, Tino JA.
Abstract : PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
|
Inhibition of PI3Kbeta (unknown origin)
|
Homo sapiens
|
380.0
nM
|
|
Journal : J Med Chem
Title : Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.
Year : 2017
Volume : 60
Issue : 12
First Page : 5193
Last Page : 5208
Authors : Liu Q, Shi Q, Marcoux D, Batt DG, Cornelius L, Qin LY, Ruan Z, Neels J, Beaudoin-Bertrand M, Srivastava AS, Li L, Cherney RJ, Gong H, Watterson SH, Weigelt C, Gillooly KM, McIntyre KW, Xie JH, Obermeier MT, Fura A, Sleczka B, Stefanski K, Fancher RM, Padmanabhan S, Rp T, Kundu I, Rajareddy K, Smith R, Hennan JK, Xing D, Fan J, Levesque PC, Ruan Q, Pitt S, Zhang R, Pedicord D, Pan J, Yarde M, Lu H, Lippy J, Goldstine C, Skala S, Rampulla RA, Mathur A, Gupta A, Arunachalam PN, Sack JS, Muckelbauer JK, Cvijic ME, Salter-Cid LM, Bhide RS, Poss MA, Hynes J, Carter PH, Macor JE, Ruepp S, Schieven GL, Tino JA.
Abstract : PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
|
Inhibition of PI3Kdelta (unknown origin) after 60 mins using fluorescein-labeled kinase tracer by HTRF assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of highly potent and selective PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 13
First Page : 2849
Last Page : 2853
Authors : Marcoux D, Qin LY, Ruan Z, Shi Q, Ruan Q, Weigelt C, Qiu H, Schieven G, Hynes J, Bhide R, Poss M, Tino J.
Abstract : Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.
|
Inhibition of PI3Kgamma (unknown origin) after 60 mins using fluorescein-labeled kinase tracer by HTRF assay
|
Homo sapiens
|
63.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of highly potent and selective PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 13
First Page : 2849
Last Page : 2853
Authors : Marcoux D, Qin LY, Ruan Z, Shi Q, Ruan Q, Weigelt C, Qiu H, Schieven G, Hynes J, Bhide R, Poss M, Tino J.
Abstract : Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.
|
Inhibition of PI3Kalpha (unknown origin) after 60 mins using fluorescein-labeled kinase tracer by HTRF assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of highly potent and selective PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 13
First Page : 2849
Last Page : 2853
Authors : Marcoux D, Qin LY, Ruan Z, Shi Q, Ruan Q, Weigelt C, Qiu H, Schieven G, Hynes J, Bhide R, Poss M, Tino J.
Abstract : Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.
|
Inhibition of PI3Kbeta (unknown origin) after 60 mins using fluorescein-labeled kinase tracer by HTRF assay
|
Homo sapiens
|
380.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of highly potent and selective PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 13
First Page : 2849
Last Page : 2853
Authors : Marcoux D, Qin LY, Ruan Z, Shi Q, Ruan Q, Weigelt C, Qiu H, Schieven G, Hynes J, Bhide R, Poss M, Tino J.
Abstract : Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.
|
Inhibition of PI3Kgamma (unknown origin) using PIP2 as substrate measured after 30 mins by HTRF assay
|
Homo sapiens
|
241.0
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of PI3Kdelta (unknown origin) using PIP2 as substrate measured after 30 mins by HTRF assay
|
Homo sapiens
|
4.3
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Antiproliferative activity against human SUDHL6 cells measured after 72 hrs by alamar blue assay
|
Homo sapiens
|
117.6
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of PI3Kbeta (unknown origin) using PIP2 as substrate measured after 30 mins by HTRF assay
|
Homo sapiens
|
669.0
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of human full length His-tagged PI3Kdelta expressed in baculovirus expression system
|
Homo sapiens
|
2.5
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of recombinant human full length His-tagged PI3Kalpha expressed in baculovirus expression system
|
Homo sapiens
|
820.0
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of recombinant human full length His-tagged PI3Kbeta expressed in insect cells
|
Homo sapiens
|
565.0
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of recombinant human full length His-tagged PI3Kgamma expressed in insect cells
|
Homo sapiens
|
89.0
nM
|
|
Journal : Eur J Med Chem
Title : SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2017
Volume : 125
First Page : 1156
Last Page : 1171
Authors : Wei M, Zhang X, Wang X, Song Z, Ding J, Meng LH, Zhang A.
Abstract : PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.
|
Inhibition of PI3K p110delta/p85alpha (unknown origin) at 100 nM using lipid substrate after 40 mins by kinase-glo luminescence assay relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1972
Last Page : 1977
Authors : Xin M, Hei YY, Zhang H, Shen Y, Zhang SQ.
Abstract : In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.
|
Inhibition of PI3K p110delta/p85alpha (unknown origin) using lipid substrate after 40 mins by kinase-glo luminescence assay
|
Homo sapiens
|
2.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1972
Last Page : 1977
Authors : Xin M, Hei YY, Zhang H, Shen Y, Zhang SQ.
Abstract : In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.
|
Antiproliferative activity against human RPMI8266 cells after 72 hrs by MTT assay
|
Homo sapiens
|
5.49
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1972
Last Page : 1977
Authors : Xin M, Hei YY, Zhang H, Shen Y, Zhang SQ.
Abstract : In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.
|
Antiproliferative activity against human Ramos cells after 72 hrs by MTT assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1972
Last Page : 1977
Authors : Xin M, Hei YY, Zhang H, Shen Y, Zhang SQ.
Abstract : In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.
|
Antiproliferative activity against human Raji cells after 72 hrs by MTT assay
|
Homo sapiens
|
9.95
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1972
Last Page : 1977
Authors : Xin M, Hei YY, Zhang H, Shen Y, Zhang SQ.
Abstract : In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced superoxide anion generation by measuring superoxide oxide dismutase inhibitable reduction of ferricytochrome c incubated for 5 mins
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactive new withanolides from the cultured soft coral Sinularia brassica.
Year : 2017
Volume : 27
Issue : 15
First Page : 3267
Last Page : 3271
Authors : Huang CY, Ahmed AF, Su JH, Sung PJ, Hwang TL, Chiang PL, Dai CF, Liaw CC, Sheu JH.
Abstract : Continuing study of the ethyl acetate (EtOAc) extract of the cultured soft coral Sinularia brassica afforded five new withanolides, sinubrasolides H-L (1-5). The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxicities of new compounds 1-5 and a known compound sinubrasolide A (6) against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of compounds 1-6 were evaluated by measuring their ability to suppress N-formyl-methionyl-leucyl-phenyl-alanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release in human neutrophils.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced superoxide anion generation by measuring superoxide oxide dismutase inhibitable reduction of ferricytochrome c at 10 uM incubated for 5 mins
|
Homo sapiens
|
102.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactive new withanolides from the cultured soft coral Sinularia brassica.
Year : 2017
Volume : 27
Issue : 15
First Page : 3267
Last Page : 3271
Authors : Huang CY, Ahmed AF, Su JH, Sung PJ, Hwang TL, Chiang PL, Dai CF, Liaw CC, Sheu JH.
Abstract : Continuing study of the ethyl acetate (EtOAc) extract of the cultured soft coral Sinularia brassica afforded five new withanolides, sinubrasolides H-L (1-5). The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxicities of new compounds 1-5 and a known compound sinubrasolide A (6) against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of compounds 1-6 were evaluated by measuring their ability to suppress N-formyl-methionyl-leucyl-phenyl-alanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release in human neutrophils.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced elastase release incubated for 5 mins in presence of MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactive new withanolides from the cultured soft coral Sinularia brassica.
Year : 2017
Volume : 27
Issue : 15
First Page : 3267
Last Page : 3271
Authors : Huang CY, Ahmed AF, Su JH, Sung PJ, Hwang TL, Chiang PL, Dai CF, Liaw CC, Sheu JH.
Abstract : Continuing study of the ethyl acetate (EtOAc) extract of the cultured soft coral Sinularia brassica afforded five new withanolides, sinubrasolides H-L (1-5). The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxicities of new compounds 1-5 and a known compound sinubrasolide A (6) against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of compounds 1-6 were evaluated by measuring their ability to suppress N-formyl-methionyl-leucyl-phenyl-alanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release in human neutrophils.
|
Antiinflammatory activity in human neutrophils assessed as inhibition of fMLP/CB-induced elastase release at 10 uM incubated for 5 mins in presence of MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide
|
Homo sapiens
|
99.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : Bioactive new withanolides from the cultured soft coral Sinularia brassica.
Year : 2017
Volume : 27
Issue : 15
First Page : 3267
Last Page : 3271
Authors : Huang CY, Ahmed AF, Su JH, Sung PJ, Hwang TL, Chiang PL, Dai CF, Liaw CC, Sheu JH.
Abstract : Continuing study of the ethyl acetate (EtOAc) extract of the cultured soft coral Sinularia brassica afforded five new withanolides, sinubrasolides H-L (1-5). The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxicities of new compounds 1-5 and a known compound sinubrasolide A (6) against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of compounds 1-6 were evaluated by measuring their ability to suppress N-formyl-methionyl-leucyl-phenyl-alanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release in human neutrophils.
|
Inhibition of PI3Kalpha (unknown origin) using PIP2:PS as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr in presence of 10 uM ATP by ADP-Glo luminescence assay
|
Homo sapiens
|
391.3
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor.
Year : 2018
Volume : 156
First Page : 831
Last Page : 846
Authors : Liang X, Li F, Chen C, Jiang Z, Wang A, Liu X, Ge J, Hu Z, Yu K, Wang W, Zou F, Liu Q, Wang B, Wang L, Zhang S, Wang Y, Liu Q, Liu J.
Abstract : PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory.
|
Inhibition of PI3Kbeta (unknown origin) using PIP2:PS as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr in presence of 50 uM ATP by ADP-Glo luminescence assay
|
Homo sapiens
|
845.5
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor.
Year : 2018
Volume : 156
First Page : 831
Last Page : 846
Authors : Liang X, Li F, Chen C, Jiang Z, Wang A, Liu X, Ge J, Hu Z, Yu K, Wang W, Zou F, Liu Q, Wang B, Wang L, Zhang S, Wang Y, Liu Q, Liu J.
Abstract : PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory.
|
Inhibition of PI3Kgamma (unknown origin) using PIP2:PS as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr in presence of 50 uM ATP by ADP-Glo luminescence assay
|
Homo sapiens
|
67.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor.
Year : 2018
Volume : 156
First Page : 831
Last Page : 846
Authors : Liang X, Li F, Chen C, Jiang Z, Wang A, Liu X, Ge J, Hu Z, Yu K, Wang W, Zou F, Liu Q, Wang B, Wang L, Zhang S, Wang Y, Liu Q, Liu J.
Abstract : PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory.
|
Inhibition of PI3Kdelta (unknown origin) using PIP2:PS as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr in presence of 50 uM ATP by ADP-Glo luminescence assay
|
Homo sapiens
|
5.9
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor.
Year : 2018
Volume : 156
First Page : 831
Last Page : 846
Authors : Liang X, Li F, Chen C, Jiang Z, Wang A, Liu X, Ge J, Hu Z, Yu K, Wang W, Zou F, Liu Q, Wang B, Wang L, Zhang S, Wang Y, Liu Q, Liu J.
Abstract : PI3Kδ, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3Kδ armory.
|
Inhibition of human recombinant PI3K-delta
|
Homo sapiens
|
2.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones by Huisgen 1,3-dipolar cycloaddition with PI3Kγ isoform selective activity.
Year : 2018
Volume : 28
Issue : 6
First Page : 1005
Last Page : 1010
Authors : Srinivas M, Singh Pathania A, Mahajan P, Verma PK, Chobe SS, Malik FA, Nargotra A, Vishwakarma RA, Sawant SD.
Abstract : A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kδ. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kγ specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kγ rather than PI3Kδ. This repositioning of scaffold from PI3Kδ to PI3Kγ isoform can be very useful from medicinal chemistry and drug discovery perspective to unravel molecular interactions of this new scaffold in different cellular pathways.
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
2.5
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Inhibition of PI3K p110delta (unknown origin) using lipid substrate after 40 mins by kinase-Glo assay
|
Homo sapiens
|
2.7
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Inhibition of PI3K p110delta (unknown origin) at 100 nM using lipid substrate after 40 mins by kinase-Glo assay relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Inhibition of PI3K p110alpha (unknown origin) using lipid substrate after 40 mins by kinase-Glo assay
|
Homo sapiens
|
306.4
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Inhibition of PI3K p110beta (unknown origin) using lipid substrate after 40 mins by kinase-Glo assay
|
Homo sapiens
|
120.1
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Inhibition of PI3K p110gamma (unknown origin) using lipid substrate after 40 mins by kinase-Glo assay
|
Homo sapiens
|
139.4
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Antiproliferative activity against human SUDHL6 cells after 72 hrs by CCK8 assay
|
Homo sapiens
|
650.0
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors.
Year : 2018
Volume : 26
Issue : 8
First Page : 2028
Last Page : 2040
Authors : Xin M, Duan W, Feng Y, Hei YY, Zhang H, Shen Y, Zhao HY, Mao S, Zhang SQ.
Abstract : In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.
|
Inhibition of PI3Kdelta (unknown origin) using Biotin-S11S12 as substrate after 120 mins in presence of ATP by ADPGlo luminescence assay
|
Homo sapiens
|
1.6
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors.
Year : 2018
Volume : 151
First Page : 9
Last Page : 17
Authors : Ma CC, Zhang CM, Tang LQ, Liu ZP.
Abstract : PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 μM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.
|
Inhibition of PI3Kdelta (unknown origin) at 1 uM using Biotin-S11S12 as substrate after 120 mins in presence of ATP by ADPGlo luminescence assay
|
Homo sapiens
|
91.91
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors.
Year : 2018
Volume : 151
First Page : 9
Last Page : 17
Authors : Ma CC, Zhang CM, Tang LQ, Liu ZP.
Abstract : PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 μM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.
|
Inhibition of PI3Kalpha (unknown origin) using Biotin-S11S12 as substrate after 60 mins in presence of ATP by Kinase Glo luminescence assay
|
Homo sapiens
|
737.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors.
Year : 2018
Volume : 151
First Page : 9
Last Page : 17
Authors : Ma CC, Zhang CM, Tang LQ, Liu ZP.
Abstract : PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 μM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.
|
Inhibition of PI3Kbeta (unknown origin) using Biotin-S11S12 as substrate after 60 mins in presence of ATP by ADPGlo luminescence assay
|
Homo sapiens
|
129.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors.
Year : 2018
Volume : 151
First Page : 9
Last Page : 17
Authors : Ma CC, Zhang CM, Tang LQ, Liu ZP.
Abstract : PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 μM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.
|
Inhibition of PI3Kgamma (unknown origin) using Biotin-S11S12 as substrate after 60 mins in presence of ATP by ADPGlo luminescence assay
|
Homo sapiens
|
139.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors.
Year : 2018
Volume : 151
First Page : 9
Last Page : 17
Authors : Ma CC, Zhang CM, Tang LQ, Liu ZP.
Abstract : PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 μM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.
|
Inhibition of PI3KCbeta/PIK3R1 (unknown origin)
|
Homo sapiens
|
600.0
nM
|
|
Journal : Eur J Med Chem
Title : Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models.
Year : 2018
Volume : 158
First Page : 405
Last Page : 413
Authors : Dumontet C, Beck G, Gardebien F, Haudecoeur R, Mathé D, Matera EL, Tourette A, Mattei E, Esmenjaud J, Boyère C, Nurisso A, Peuchmaur M, Pérès B, Bouchaud G, Magnan A, Monneret G, Boumendjel A.
Abstract : Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.
|
Inhibition of PI3KCdelta/PIK3R1 (unknown origin)
|
Homo sapiens
|
17.0
nM
|
|
Journal : Eur J Med Chem
Title : Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models.
Year : 2018
Volume : 158
First Page : 405
Last Page : 413
Authors : Dumontet C, Beck G, Gardebien F, Haudecoeur R, Mathé D, Matera EL, Tourette A, Mattei E, Esmenjaud J, Boyère C, Nurisso A, Peuchmaur M, Pérès B, Bouchaud G, Magnan A, Monneret G, Boumendjel A.
Abstract : Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.
|
Inhibition of PI3KCgamma (unknown origin)
|
Homo sapiens
|
250.0
nM
|
|
Journal : Eur J Med Chem
Title : Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models.
Year : 2018
Volume : 158
First Page : 405
Last Page : 413
Authors : Dumontet C, Beck G, Gardebien F, Haudecoeur R, Mathé D, Matera EL, Tourette A, Mattei E, Esmenjaud J, Boyère C, Nurisso A, Peuchmaur M, Pérès B, Bouchaud G, Magnan A, Monneret G, Boumendjel A.
Abstract : Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-4.09
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of PI3K alpha (unknown origin) using lipid substrate measured after 40 mins in presence of ATP by Kinase-Glo plus reagent based luminescence assay
|
Homo sapiens
|
583.0
nM
|
|
Journal : Bioorg Med Chem
Title : Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.
Year : 2019
Volume : 27
Issue : 20
First Page : 114930
Last Page : 114930
Authors : Hei YY, Zhang SQ, Feng Y, Wang J, Duan W, Zhang H, Mao S, Sun H, Xin M.
Abstract : Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC<sub>50</sub> = 4.5 nM), PI3Kβ (IC<sub>50</sub> = 4.5 nM), PI3Kγ (IC<sub>50</sub> = 4.5 nM), PI3Kδ (IC<sub>50</sub> = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC<sub>50</sub> values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKT<sup>S473</sup> in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.
|
Inhibition of PI3K beta (unknown origin) using lipid substrate measured after 40 mins in presence of ATP by Kinase-Glo plus reagent based luminescence assay
|
Homo sapiens
|
134.0
nM
|
|
Journal : Bioorg Med Chem
Title : Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.
Year : 2019
Volume : 27
Issue : 20
First Page : 114930
Last Page : 114930
Authors : Hei YY, Zhang SQ, Feng Y, Wang J, Duan W, Zhang H, Mao S, Sun H, Xin M.
Abstract : Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC<sub>50</sub> = 4.5 nM), PI3Kβ (IC<sub>50</sub> = 4.5 nM), PI3Kγ (IC<sub>50</sub> = 4.5 nM), PI3Kδ (IC<sub>50</sub> = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC<sub>50</sub> values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKT<sup>S473</sup> in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.
|
Inhibition of PI3K gamma (unknown origin) using lipid substrate measured after 40 mins in presence of ATP by Kinase-Glo plus reagent based luminescence assay
|
Homo sapiens
|
381.0
nM
|
|
Journal : Bioorg Med Chem
Title : Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.
Year : 2019
Volume : 27
Issue : 20
First Page : 114930
Last Page : 114930
Authors : Hei YY, Zhang SQ, Feng Y, Wang J, Duan W, Zhang H, Mao S, Sun H, Xin M.
Abstract : Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC<sub>50</sub> = 4.5 nM), PI3Kβ (IC<sub>50</sub> = 4.5 nM), PI3Kγ (IC<sub>50</sub> = 4.5 nM), PI3Kδ (IC<sub>50</sub> = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC<sub>50</sub> values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKT<sup>S473</sup> in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.
|
Inhibition of PI3K delta (unknown origin) using lipid substrate measured after 40 mins in presence of ATP by Kinase-Glo plus reagent based luminescence assay
|
Homo sapiens
|
3.1
nM
|
|
Journal : Bioorg Med Chem
Title : Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.
Year : 2019
Volume : 27
Issue : 20
First Page : 114930
Last Page : 114930
Authors : Hei YY, Zhang SQ, Feng Y, Wang J, Duan W, Zhang H, Mao S, Sun H, Xin M.
Abstract : Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC<sub>50</sub> = 4.5 nM), PI3Kβ (IC<sub>50</sub> = 4.5 nM), PI3Kγ (IC<sub>50</sub> = 4.5 nM), PI3Kδ (IC<sub>50</sub> = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC<sub>50</sub> values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKT<sup>S473</sup> in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.
|
Inhibition of PIK3CD (unknown origin)
|
Homo sapiens
|
19.0
nM
|
|
Journal : J Med Chem
Title : Why Some Targets Benefit from beyond Rule of Five Drugs.
Year : 2019
Volume : 62
Issue : 22
First Page : 10005
Last Page : 10025
Authors : Egbert M, Whitty A, Keserű GM, Vajda S.
Abstract : Beyond rule-of-five (bRo5) compounds are increasingly used in drug discovery. Here we analyze 37 target proteins that have bRo5 drugs or clinical candidates. Targets can benefit from bRo5 drugs if they have "complex" hot spot structure with four or more hots spots, including some strong ones. Complex I targets show positive correlation between binding affinity and molecular weight. These targets are conventionally druggable, but reaching additional hot spots enables improved pharmaceutical properties. Complex II targets, mostly protein kinases, also have strong hot spots but show no correlation between affinity and ligand molecular weight, and the primary motivation for creating larger drugs is to increase selectivity. Each target considered as complex III has some specific reason for requiring bRo5 drugs. Finally, targets with "simple" hot spot structure, i.e., three or fewer weak hot spots, must use larger compounds that interact with surfaces beyond the hot spot region to achieve acceptable affinity.
|
Inhibition of human N-terminal His-tagged PI3Kalpha/p85alpha expressed in Spodoptera frugiperda using phosphatidylinositol as substrate
|
Homo sapiens
|
800.0
nM
|
|
Journal : Eur J Med Chem
Title : Targeting the immunity protein kinases for immuno-oncology.
Year : 2019
Volume : 163
First Page : 413
Last Page : 427
Authors : Yuan X, Wu H, Bu H, Zhou J, Zhang H.
Abstract : With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.
|
Inhibition of PI3Kgamma (unknown origin)
|
Homo sapiens
|
63.0
nM
|
|
Journal : Eur J Med Chem
Title : Targeting the immunity protein kinases for immuno-oncology.
Year : 2019
Volume : 163
First Page : 413
Last Page : 427
Authors : Yuan X, Wu H, Bu H, Zhou J, Zhang H.
Abstract : With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : Targeting the immunity protein kinases for immuno-oncology.
Year : 2019
Volume : 163
First Page : 413
Last Page : 427
Authors : Yuan X, Wu H, Bu H, Zhou J, Zhang H.
Abstract : With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.
|
Inhibition of PI3Kdelta in basophil derived from B-cell malignant patient
|
Homo sapiens
|
2.5
nM
|
|
Journal : J Med Chem
Title : Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.
Year : 2019
Volume : 62
Issue : 10
First Page : 4783
Last Page : 4814
Authors : Perry MWD, Abdulai R, Mogemark M, Petersen J, Thomas MJ, Valastro B, Westin Eriksson A.
Abstract : Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
|
Inhibition of PI3Kgamma in basophil derived from B-cell malignant patient
|
Homo sapiens
|
89.0
nM
|
|
Journal : J Med Chem
Title : Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.
Year : 2019
Volume : 62
Issue : 10
First Page : 4783
Last Page : 4814
Authors : Perry MWD, Abdulai R, Mogemark M, Petersen J, Thomas MJ, Valastro B, Westin Eriksson A.
Abstract : Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
|
Cytotoxicity against basophil derived from B-cell malignant patient by cell-titer aqueous one solution cell proliferation assay
|
Homo sapiens
|
846.0
nM
|
|
Journal : J Med Chem
Title : Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.
Year : 2019
Volume : 62
Issue : 10
First Page : 4783
Last Page : 4814
Authors : Perry MWD, Abdulai R, Mogemark M, Petersen J, Thomas MJ, Valastro B, Westin Eriksson A.
Abstract : Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
|
Inhibition of Vps34 (unknown origin)
|
Homo sapiens
|
980.0
nM
|
|
Journal : J Med Chem
Title : Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.
Year : 2019
Volume : 62
Issue : 10
First Page : 4783
Last Page : 4814
Authors : Perry MWD, Abdulai R, Mogemark M, Petersen J, Thomas MJ, Valastro B, Westin Eriksson A.
Abstract : Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
|
Inhibition of N-terminal His6-tagged recombinant full length human p110beta/untagged recombinant full length human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate measured after 80 mins by transcreener fluorescence polarization assay
|
Homo sapiens
|
293.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of recombinant human full-length His-tagged PI3K p110gamma expressed in baculovirus expression system using PIP2 as substrate measured after 80 mins by transcreener fluorescence polarization assay
|
Homo sapiens
|
104.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of N-terminal His6-tagged recombinant full length human p110delta/untagged recombinant full length human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2 as substrate measured after 80 mins by transcreener fluorescence polarization assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of recombinant human full-length His-tagged PI3K p110gamma expressed in baculovirus expression system at 1 uM using PIP2 as substrate measured after 80 mins by transcreener fluorescence polarization assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of N-terminal His6-tagged recombinant full length human p110delta/untagged recombinant full length human p85alpha expressed in baculovirus infected Sf21 insect cells at 1 uM using PIP2 as substrate measured after 80 mins by transcreener fluorescence polarization assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of N-terminal His6-tagged recombinant full length human p110beta/untagged recombinant full length human p85alpha expressed in baculovirus infected Sf21 insect cells at 1 uM using PIP2 as substrate measured after 80 mins by transcreener fluorescence polarization assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of PI3Kgamma in rat RAW264.7 cells assessed as reduction in C5a-stimulated AKT phosphorylation at Ser473 residue preincubated for 30 mins followed by C5a-stimulation and measured after 5 mins
|
Rattus norvegicus
|
337.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of PI3Kdelta in human Ramos cells assessed as reduction in antihuman IgM-stimulated AKT phosphorylation at Ser473 residue preincubated for 60 mins followed by antihuman IgM stimulation and measured after 15 mins
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
Year : 2019
Volume : 62
Issue : 10
First Page : 4936
Last Page : 4948
Authors : Jia H, Dai G, Su W, Xiao K, Weng J, Zhang Z, Wang Q, Yuan T, Shi F, Zhang Z, Chen W, Sai Y, Wang J, Li X, Cai Y, Yu J, Ren P, Venable J, Rao T, Edwards JP, Bembenek SD.
Abstract : An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
|
Inhibition of His-tagged recombinant human PI3K p110delta/p85alpha expressed in Baculovirus expression system
|
Homo sapiens
|
19.0
nM
|
|
Journal : J Med Chem
Title : The Exploration of Chirality for Improved Druggability within the Human Kinome.
Year : 2020
Volume : 63
Issue : 2
First Page : 441
Last Page : 469
Authors : Saha D, Kharbanda A, Yan W, Lakkaniga NR, Frett B, Li HY.
Abstract : Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.
|
Inhibition of PI3Kdelta (unknown origin) using PIP2 as substrate after 2 hrs by ADP-Glo assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : MedChemComm
Title : Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.
Year : 2019
Volume : 10
Issue : 3
First Page : 413
Last Page : 420
Authors : Ma X, Fang F, Tao Q, Shen L, Zhong G, Qiao T, Lv X, Li J.
Abstract : A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized <i>via</i> the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC<sub>50</sub> values against PI3Kδ, along with low micromolar to submicromolar GI<sub>50</sub> values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC<sub>50</sub> = 6.3 nM) and anti-proliferative activity (GI<sub>50</sub> = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, <i>in vitro</i> metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.
|
Inhibition of PI3Kalpha (unknown origin) using PIP2 as substrate after 2 hrs by ADP-Glo assay
|
Homo sapiens
|
822.0
nM
|
|
Journal : MedChemComm
Title : Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.
Year : 2019
Volume : 10
Issue : 3
First Page : 413
Last Page : 420
Authors : Ma X, Fang F, Tao Q, Shen L, Zhong G, Qiao T, Lv X, Li J.
Abstract : A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized <i>via</i> the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC<sub>50</sub> values against PI3Kδ, along with low micromolar to submicromolar GI<sub>50</sub> values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC<sub>50</sub> = 6.3 nM) and anti-proliferative activity (GI<sub>50</sub> = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, <i>in vitro</i> metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.
|
Inhibition of PI3Kbeta (unknown origin) using PIP2 as substrate after 2 hrs by ADP-Glo assay
|
Homo sapiens
|
281.0
nM
|
|
Journal : MedChemComm
Title : Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.
Year : 2019
Volume : 10
Issue : 3
First Page : 413
Last Page : 420
Authors : Ma X, Fang F, Tao Q, Shen L, Zhong G, Qiao T, Lv X, Li J.
Abstract : A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized <i>via</i> the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC<sub>50</sub> values against PI3Kδ, along with low micromolar to submicromolar GI<sub>50</sub> values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC<sub>50</sub> = 6.3 nM) and anti-proliferative activity (GI<sub>50</sub> = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, <i>in vitro</i> metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.
|
Inhibition of PI3Kgamma (unknown origin) using PIP2 as substrate after 2 hrs by ADP-Glo assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : MedChemComm
Title : Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.
Year : 2019
Volume : 10
Issue : 3
First Page : 413
Last Page : 420
Authors : Ma X, Fang F, Tao Q, Shen L, Zhong G, Qiao T, Lv X, Li J.
Abstract : A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized <i>via</i> the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC<sub>50</sub> values against PI3Kδ, along with low micromolar to submicromolar GI<sub>50</sub> values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC<sub>50</sub> = 6.3 nM) and anti-proliferative activity (GI<sub>50</sub> = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, <i>in vitro</i> metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.
|
Inhibition of His6-tagged recombinant full length human N-terminal PI3Kbeta expressed in baculovirus infected Sf21 cells using lipid substrate incubated for 2 hrs by ADP-Glo assay
|
Homo sapiens
|
154.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies.
Year : 2019
Volume : 170
First Page : 112
Last Page : 125
Authors : Ma X, Wei J, Wang C, Gu D, Hu Y, Sheng R.
Abstract : A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. In subsequent biological evaluation, S-63 (IC50: 4.6 nM) and S-71 (IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, respectively, to that of idelalisib. Additionally, both S-63 (GI50: 33.2 nM) and S-71 (GI50: 15.9 nM) exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib. Moreover, both S-63 and S-71 exhibited excellent PI3Kδ selectivity. In the further in vivo pharmacokinetic (PK) study, S-63 displayed a good plasma exposure and an acceptable oral bioavailability of 29.2%. By virtue of its biological performance, S-63 merits further development as a potential therapeutic agent for battling B-cell-mediated malignancies.
|
Inhibition of His-tagged recombinant human PI3K p110delta/p85alpha using lipid substrate incubated for 2 hrs by ADP-Glo assay
|
Homo sapiens
|
1.8
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies.
Year : 2019
Volume : 170
First Page : 112
Last Page : 125
Authors : Ma X, Wei J, Wang C, Gu D, Hu Y, Sheng R.
Abstract : A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. In subsequent biological evaluation, S-63 (IC50: 4.6 nM) and S-71 (IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, respectively, to that of idelalisib. Additionally, both S-63 (GI50: 33.2 nM) and S-71 (GI50: 15.9 nM) exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib. Moreover, both S-63 and S-71 exhibited excellent PI3Kδ selectivity. In the further in vivo pharmacokinetic (PK) study, S-63 displayed a good plasma exposure and an acceptable oral bioavailability of 29.2%. By virtue of its biological performance, S-63 merits further development as a potential therapeutic agent for battling B-cell-mediated malignancies.
|
Inhibition of His-tagged recombinant human full length PI3K p110gamma expressed in baculovirus expression system using lipid substrate incubated for 2 hrs by ADP-Glo assay
|
Homo sapiens
|
63.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies.
Year : 2019
Volume : 170
First Page : 112
Last Page : 125
Authors : Ma X, Wei J, Wang C, Gu D, Hu Y, Sheng R.
Abstract : A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. In subsequent biological evaluation, S-63 (IC50: 4.6 nM) and S-71 (IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, respectively, to that of idelalisib. Additionally, both S-63 (GI50: 33.2 nM) and S-71 (GI50: 15.9 nM) exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib. Moreover, both S-63 and S-71 exhibited excellent PI3Kδ selectivity. In the further in vivo pharmacokinetic (PK) study, S-63 displayed a good plasma exposure and an acceptable oral bioavailability of 29.2%. By virtue of its biological performance, S-63 merits further development as a potential therapeutic agent for battling B-cell-mediated malignancies.
|
Antiproliferative activity against human TMD8 cells
|
Homo sapiens
|
795.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.
Year : 2019
Volume : 29
Issue : 11
First Page : 1313
Last Page : 1319
Authors : Bahekar R, Dave B, Soman S, Patel D, Chopade R, Funde R, Kumar J, Sachchidanand S, Giri P, Chatterjee A, Mahapatra J, Vyas P, Ghoshdastidar K, Bandyopadhyay D, Desai RC.
Abstract : PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
|
Inhibition of human PI3Kdelta using PIP2 as substrate at 100 nM after 1 hr relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.
Year : 2019
Volume : 29
Issue : 11
First Page : 1313
Last Page : 1319
Authors : Bahekar R, Dave B, Soman S, Patel D, Chopade R, Funde R, Kumar J, Sachchidanand S, Giri P, Chatterjee A, Mahapatra J, Vyas P, Ghoshdastidar K, Bandyopadhyay D, Desai RC.
Abstract : PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
|
Inhibition of human PI3Kdelta using PIP2 as substrate after 1 hr
|
Homo sapiens
|
2.1
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.
Year : 2019
Volume : 29
Issue : 11
First Page : 1313
Last Page : 1319
Authors : Bahekar R, Dave B, Soman S, Patel D, Chopade R, Funde R, Kumar J, Sachchidanand S, Giri P, Chatterjee A, Mahapatra J, Vyas P, Ghoshdastidar K, Bandyopadhyay D, Desai RC.
Abstract : PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
|
Inhibition of human PI3Kalpha using PIP2 as substrate after 1 hr
|
Homo sapiens
|
831.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.
Year : 2019
Volume : 29
Issue : 11
First Page : 1313
Last Page : 1319
Authors : Bahekar R, Dave B, Soman S, Patel D, Chopade R, Funde R, Kumar J, Sachchidanand S, Giri P, Chatterjee A, Mahapatra J, Vyas P, Ghoshdastidar K, Bandyopadhyay D, Desai RC.
Abstract : PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
|
Inhibition of human PI3Kbeta using PIP2 as substrate after 1 hr
|
Homo sapiens
|
571.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.
Year : 2019
Volume : 29
Issue : 11
First Page : 1313
Last Page : 1319
Authors : Bahekar R, Dave B, Soman S, Patel D, Chopade R, Funde R, Kumar J, Sachchidanand S, Giri P, Chatterjee A, Mahapatra J, Vyas P, Ghoshdastidar K, Bandyopadhyay D, Desai RC.
Abstract : PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
|
Inhibition of human PI3Kgamma using PIP2 as substrate after 1 hr
|
Homo sapiens
|
92.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors.
Year : 2019
Volume : 29
Issue : 11
First Page : 1313
Last Page : 1319
Authors : Bahekar R, Dave B, Soman S, Patel D, Chopade R, Funde R, Kumar J, Sachchidanand S, Giri P, Chatterjee A, Mahapatra J, Vyas P, Ghoshdastidar K, Bandyopadhyay D, Desai RC.
Abstract : PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
|
Inhibition of PI3K delta (unknown origin) using phosphatidyl inositol as substrate measured after 60 mins in presence of ATP by Kinase-Glo Plus reagent-based luminescence assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors.
Year : 2019
Volume : 27
Issue : 19
First Page : 115035
Last Page : 115035
Authors : Feng Y, Duan W, Fan S, Zhang H, Zhang SQ, Xin M.
Abstract : PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC<sub>50</sub> values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC<sub>50</sub> = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC<sub>50</sub> values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKT<sup>S473</sup> phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.
|
Inhibition of PI3K alpha (unknown origin) using phosphatidyl inositol as substrate measured after 60 mins in presence of ATP by Kinase-Glo Plus reagent-based luminescence assay
|
Homo sapiens
|
177.2
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors.
Year : 2019
Volume : 27
Issue : 19
First Page : 115035
Last Page : 115035
Authors : Feng Y, Duan W, Fan S, Zhang H, Zhang SQ, Xin M.
Abstract : PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC<sub>50</sub> values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC<sub>50</sub> = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC<sub>50</sub> values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKT<sup>S473</sup> phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.
|
Inhibition of PI3K beta (unknown origin) using phosphatidyl inositol as substrate measured after 60 mins in presence of ATP by Kinase-Glo Plus reagent-based luminescence assay
|
Homo sapiens
|
139.1
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors.
Year : 2019
Volume : 27
Issue : 19
First Page : 115035
Last Page : 115035
Authors : Feng Y, Duan W, Fan S, Zhang H, Zhang SQ, Xin M.
Abstract : PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC<sub>50</sub> values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC<sub>50</sub> = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC<sub>50</sub> values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKT<sup>S473</sup> phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.
|
Inhibition of PI3K gamma (unknown origin) using phosphatidyl inositol as substrate measured after 60 mins in presence of ATP by Kinase-Glo Plus reagent-based luminescence assay
|
Homo sapiens
|
145.3
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors.
Year : 2019
Volume : 27
Issue : 19
First Page : 115035
Last Page : 115035
Authors : Feng Y, Duan W, Fan S, Zhang H, Zhang SQ, Xin M.
Abstract : PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC<sub>50</sub> values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC<sub>50</sub> = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC<sub>50</sub> values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKT<sup>S473</sup> phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.
|
Antiproliferative activity against human SUDHL6 cells by MTT assay
|
Homo sapiens
|
33.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors.
Year : 2019
Volume : 27
Issue : 19
First Page : 115035
Last Page : 115035
Authors : Feng Y, Duan W, Fan S, Zhang H, Zhang SQ, Xin M.
Abstract : PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC<sub>50</sub> values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC<sub>50</sub> = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC<sub>50</sub> values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKT<sup>S473</sup> phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.
|
Inhibition of PI3Kdelta (unknown origin) using biotin-PIP3 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by fluorescence polarization assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.
Year : 2019
Volume : 62
Issue : 22
First Page : 10402
Last Page : 10422
Authors : Barnes L, Blaber H, Brooks DTK, Byers L, Buckley D, Byron ZC, Chilvers RG, Cochrane L, Cooney E, Damian HA, Francis L, Fu He D, Grace JMJ, Green HJ, Hogarth EJP, Jusu L, Killalea CE, King O, Lambert J, Lee ZJ, Lima NS, Long CL, Mackinnon ML, Mahdy S, Matthews-Wright J, Millward MJ, Meehan MF, Merrett C, Morrison L, Parke HRI, Payne C, Payne L, Pike C, Seal A, Senior AJ, Smith KM, Stanelyte K, Stillibrand J, Szpara R, Taday FFH, Threadgould AM, Trainor RJ, Waters J, Williams O, Wong CKW, Wood K, Barton N, Gruszka A, Henley Z, Rowedder JE, Cookson R, Jones KL, Nadin A, Smith IE, Macdonald SJF, Nortcliffe A.
Abstract : Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
|
Inhibition of PI3Kgamma (unknown origin) using biotin-PIP3 as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by fluorescence polarization assay
|
Homo sapiens
|
199.53
nM
|
|
Journal : J Med Chem
Title : Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.
Year : 2019
Volume : 62
Issue : 22
First Page : 10402
Last Page : 10422
Authors : Barnes L, Blaber H, Brooks DTK, Byers L, Buckley D, Byron ZC, Chilvers RG, Cochrane L, Cooney E, Damian HA, Francis L, Fu He D, Grace JMJ, Green HJ, Hogarth EJP, Jusu L, Killalea CE, King O, Lambert J, Lee ZJ, Lima NS, Long CL, Mackinnon ML, Mahdy S, Matthews-Wright J, Millward MJ, Meehan MF, Merrett C, Morrison L, Parke HRI, Payne C, Payne L, Pike C, Seal A, Senior AJ, Smith KM, Stanelyte K, Stillibrand J, Szpara R, Taday FFH, Threadgould AM, Trainor RJ, Waters J, Williams O, Wong CKW, Wood K, Barton N, Gruszka A, Henley Z, Rowedder JE, Cookson R, Jones KL, Nadin A, Smith IE, Macdonald SJF, Nortcliffe A.
Abstract : Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
|
Anti-inflammatory activity in FMLP/CB-stimulated human neutrophils assessed as inhibition of superoxide generation at 10 uM preincubated for 5 mins followed by cytochalasin B and FMLP stimulation for 3 mins and 10 mins respectively by ferricytochrome c reduction based assay relative to control
|
Homo sapiens
|
103.0
%
|
|
Journal : J Nat Prod
Title : Bioactive Isoprenoid-Derived Natural Products from a Dongsha Atoll Soft Coral Sinularia erecta.
Year : 2016
Volume : 79
Issue : 5
First Page : 1339
Last Page : 1346
Authors : Huang CY, Tseng YJ, Chokkalingam U, Hwang TL, Hsu CH, Dai CF, Sung PJ, Sheu JH.
Abstract : Four new isoprenoids, including two norcembranoids sinulerectols A and B (1 and 2), a cembranoid sinulerectol C (3), and a degraded cembranoid sinulerectadione (4), along with three known isoprenoids, an unnamed norcembrene (5), sinularectin (6), and ineleganolide (7), and a known nitrogen-containing compound (Z)-N-[2-(4-hydroxyphenyl)ethyl]-3-methyldodec-2-enamide (8), were isolated from an extract of the marine soft coral Sinularia erecta. The structure of sinularectin (6) was revised, too. Compounds 3, 4, and 8 exhibited inhibitory activity against the proliferation of a limited panel of cancer cell lines, whereas 1, 2, and 8 displayed potent anti-inflammatory activity in fMLP/CB-stimulated human neutrophils.
|
Anti-inflammatory activity in FMLP/CB-stimulated human neutrophils assessed as inhibition of superoxide generation preincubated for 5 mins followed by cytochalasin B and FMLP stimulation for 3 mins and 10 mins respectively by ferricytochrome c reduction based assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : J Nat Prod
Title : Bioactive Isoprenoid-Derived Natural Products from a Dongsha Atoll Soft Coral Sinularia erecta.
Year : 2016
Volume : 79
Issue : 5
First Page : 1339
Last Page : 1346
Authors : Huang CY, Tseng YJ, Chokkalingam U, Hwang TL, Hsu CH, Dai CF, Sung PJ, Sheu JH.
Abstract : Four new isoprenoids, including two norcembranoids sinulerectols A and B (1 and 2), a cembranoid sinulerectol C (3), and a degraded cembranoid sinulerectadione (4), along with three known isoprenoids, an unnamed norcembrene (5), sinularectin (6), and ineleganolide (7), and a known nitrogen-containing compound (Z)-N-[2-(4-hydroxyphenyl)ethyl]-3-methyldodec-2-enamide (8), were isolated from an extract of the marine soft coral Sinularia erecta. The structure of sinularectin (6) was revised, too. Compounds 3, 4, and 8 exhibited inhibitory activity against the proliferation of a limited panel of cancer cell lines, whereas 1, 2, and 8 displayed potent anti-inflammatory activity in fMLP/CB-stimulated human neutrophils.
|
Anti-inflammatory activity in FMLP/CB-stimulated human neutrophils assessed as inhibition of elastase release at 10 uM preincubated for 5 mins followed by FMLP/CB stimulation for 10 mins using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as substrate relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : J Nat Prod
Title : Bioactive Isoprenoid-Derived Natural Products from a Dongsha Atoll Soft Coral Sinularia erecta.
Year : 2016
Volume : 79
Issue : 5
First Page : 1339
Last Page : 1346
Authors : Huang CY, Tseng YJ, Chokkalingam U, Hwang TL, Hsu CH, Dai CF, Sung PJ, Sheu JH.
Abstract : Four new isoprenoids, including two norcembranoids sinulerectols A and B (1 and 2), a cembranoid sinulerectol C (3), and a degraded cembranoid sinulerectadione (4), along with three known isoprenoids, an unnamed norcembrene (5), sinularectin (6), and ineleganolide (7), and a known nitrogen-containing compound (Z)-N-[2-(4-hydroxyphenyl)ethyl]-3-methyldodec-2-enamide (8), were isolated from an extract of the marine soft coral Sinularia erecta. The structure of sinularectin (6) was revised, too. Compounds 3, 4, and 8 exhibited inhibitory activity against the proliferation of a limited panel of cancer cell lines, whereas 1, 2, and 8 displayed potent anti-inflammatory activity in fMLP/CB-stimulated human neutrophils.
|
Anti-inflammatory activity in FMLP/CB-stimulated human neutrophils assessed as inhibition of elastase release preincubated for 5 mins followed by FMLP/CB stimulation for 10 mins using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as substrate
|
Homo sapiens
|
300.0
nM
|
|
Journal : J Nat Prod
Title : Bioactive Isoprenoid-Derived Natural Products from a Dongsha Atoll Soft Coral Sinularia erecta.
Year : 2016
Volume : 79
Issue : 5
First Page : 1339
Last Page : 1346
Authors : Huang CY, Tseng YJ, Chokkalingam U, Hwang TL, Hsu CH, Dai CF, Sung PJ, Sheu JH.
Abstract : Four new isoprenoids, including two norcembranoids sinulerectols A and B (1 and 2), a cembranoid sinulerectol C (3), and a degraded cembranoid sinulerectadione (4), along with three known isoprenoids, an unnamed norcembrene (5), sinularectin (6), and ineleganolide (7), and a known nitrogen-containing compound (Z)-N-[2-(4-hydroxyphenyl)ethyl]-3-methyldodec-2-enamide (8), were isolated from an extract of the marine soft coral Sinularia erecta. The structure of sinularectin (6) was revised, too. Compounds 3, 4, and 8 exhibited inhibitory activity against the proliferation of a limited panel of cancer cell lines, whereas 1, 2, and 8 displayed potent anti-inflammatory activity in fMLP/CB-stimulated human neutrophils.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
30.29
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.69
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-0.9913
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.18
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.23
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.18
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.23
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of human full-length recombinant His-tagged PI3K p110delta/p85alpha expressed in baculovirus expression system using PIP2 as substrate measured after 2 hrs by ADP-Glo luminescence assay
|
Homo sapiens
|
3.4
nM
|
|
Journal : Eur J Med Chem
Title : Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation.
Year : 2020
Volume : 191
First Page : 112143
Last Page : 112143
Authors : Tao Q,Chen Y,Liang X,Hu Y,Li J,Fang F,Wang H,Meng C,Liang J,Ma X,Gui S
Abstract : Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kβ. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.
|
Inhibition of human PI3Kdelta using substrate PIP2:PS and ATP incubated for 1 hr by ADP-Glo assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.
Year : 2020
Volume : 63
Issue : 22
First Page : 13973
Last Page : 13993
Authors : Li F,Liang X,Jiang Z,Wang A,Wang J,Chen C,Wang W,Zou F,Qi Z,Liu Q,Hu Z,Cao J,Wu H,Wang B,Wang L,Liu J,Liu Q
Abstract : Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor ( S )-18. In the biochemical assay, ( S )-18 inhibits PI3Kδ (IC = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). ( S )-18 also achieves good selectivity over other protein kinases in the kinome (S-score (35) = 0.015). In the cell, ( S )-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, ( S )-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC > 10 μM). In vivo, ( S )-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that ( S )-18 might be a new potential therapeutic candidate for COPD.
|
Anticancer activity against human SUDHL-6 assessed as inhibition of ATP level measured after 96 hrs by CellTiter-Glo reagent assay
|
Homo sapiens
|
22.5
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.
Year : 2020
Volume : 63
Issue : 23.0
First Page : 14700
Last Page : 14723
Authors : Shukla MR,Patra S,Verma M,Sadasivam G,Jana N,Mahangare SJ,Vidhate P,Lagad D,Tarage A,Cheemala M,Kulkarni C,Bhagwat S,Chaudhari VD,Sayyed M,Pachpute V,Phadtare R,Gole G,Phukan S,Sunkara B,Samant C,Shingare M,Naik A,Trivedi S,Marisetti AK,Reddy M,Gholve M,Mahajan N,Sabde S,Patil V,Modi D,Mehta M,Nigade P,Tamane K,Tota S,Goyal H,Volam H,Pawar S,Ahirrao P,Dinchhana L,Mallurwar S,Akarte A,Bokare A,Kanhere R,Reddy N,Koul S,Dandekar M,Singh M,Bernstein PR,Narasimham L,Bhonde M,Gundu J,Goel R,Kulkarni S,Sharma S,Kamboj RK,Palle VP
Abstract : PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
|
Anticancer activity against human OCILY10 assessed as inhibition of ATP level measured after 96 hrs by CellTiter-Glo reagent assay
|
Homo sapiens
|
31.9
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.
Year : 2020
Volume : 63
Issue : 23.0
First Page : 14700
Last Page : 14723
Authors : Shukla MR,Patra S,Verma M,Sadasivam G,Jana N,Mahangare SJ,Vidhate P,Lagad D,Tarage A,Cheemala M,Kulkarni C,Bhagwat S,Chaudhari VD,Sayyed M,Pachpute V,Phadtare R,Gole G,Phukan S,Sunkara B,Samant C,Shingare M,Naik A,Trivedi S,Marisetti AK,Reddy M,Gholve M,Mahajan N,Sabde S,Patil V,Modi D,Mehta M,Nigade P,Tamane K,Tota S,Goyal H,Volam H,Pawar S,Ahirrao P,Dinchhana L,Mallurwar S,Akarte A,Bokare A,Kanhere R,Reddy N,Koul S,Dandekar M,Singh M,Bernstein PR,Narasimham L,Bhonde M,Gundu J,Goel R,Kulkarni S,Sharma S,Kamboj RK,Palle VP
Abstract : PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
|
Anticancer activity against human TMD8 assessed as inhibition of ATP level measured after 96 hrs by CellTiter-Glo reagent assay
|
Homo sapiens
|
7.3
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.
Year : 2020
Volume : 63
Issue : 23.0
First Page : 14700
Last Page : 14723
Authors : Shukla MR,Patra S,Verma M,Sadasivam G,Jana N,Mahangare SJ,Vidhate P,Lagad D,Tarage A,Cheemala M,Kulkarni C,Bhagwat S,Chaudhari VD,Sayyed M,Pachpute V,Phadtare R,Gole G,Phukan S,Sunkara B,Samant C,Shingare M,Naik A,Trivedi S,Marisetti AK,Reddy M,Gholve M,Mahajan N,Sabde S,Patil V,Modi D,Mehta M,Nigade P,Tamane K,Tota S,Goyal H,Volam H,Pawar S,Ahirrao P,Dinchhana L,Mallurwar S,Akarte A,Bokare A,Kanhere R,Reddy N,Koul S,Dandekar M,Singh M,Bernstein PR,Narasimham L,Bhonde M,Gundu J,Goel R,Kulkarni S,Sharma S,Kamboj RK,Palle VP
Abstract : PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
4.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of PI3Kbeta (unknown origin)
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of PI3Kgamma (unknown origin)
|
Homo sapiens
|
245.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Antiproliferative activity against human SU-DHL-6 assessed as reduction in cell growth by MTS assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Antiproliferative activity against human JeKo-1 assessed as reduction in cell growth by MTS assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of recombinant human His-tagged PI3Kdelta expressed in baculovirus expression system using PIP2:PS as substrate incubated for 1 hr by invitrogen adapta assay
|
Homo sapiens
|
2.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of recombinant human His-tagged PI3Kalpha expressed in insect cell expression system using PIP2:PS as substrate incubated for 1 hr by invitrogen adapta assay
|
Homo sapiens
|
820.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of recombinant human His-tagged PI3Kbeta expressed in insect cell expression system using PIP2:PS as substrate incubated for 1 hr by invitrogen adapta assay
|
Homo sapiens
|
565.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of recombinant human His-tagged PI3Kgamma expressed in baculovirus expression system using PIP2:PS as substrate incubated for 1 hr by invitrogen adapta assay
|
Homo sapiens
|
89.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors.
Year : 2020
Volume : 30
Issue : 20
First Page : 127479
Last Page : 127479
Authors : Wang NY,Zuo WQ,Hu R,Wang WL,Zhu YX,Xu Y,Yu LT,Liu ZH
Abstract : Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
|
Inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
2.5
nM
|
|
|
Inhibition of recombinant full-length human His-tagged PI3Kalpha expressed in insect cells by Selectscreen kinase assay
|
Homo sapiens
|
820.0
nM
|
|
|
Inhibition of recombinant full-length human His-tagged PI3Kbeta expressed in insect cells by Selectscreen kinase assay
|
Homo sapiens
|
564.0
nM
|
|
|
Inhibition of recombinant full-length human His-tagged PI3Kgamma expressed in baculovirus expression system by Selectscreen kinase assay
|
Homo sapiens
|
89.0
nM
|
|
|
Inhibition of PI3Kdelta (unknown origin) by Selectscreen kinase assay
|
Homo sapiens
|
2.5
nM
|
|
|
Inhibition of recombinant human full length N-terminal His-tagged p110alpha/p85alpha expressed in baculovirus expression system measured after 60 mins in presence of ATP by ATP-competitive binding assay
|
Homo sapiens
|
409.0
nM
|
|
|
Inhibition of recombinant human full length His-tagged p110beta expressed in baculovirus expression system measured after 60 mins in presence of ATP by ATP-competitive binding assay
|
Homo sapiens
|
613.0
nM
|
|
|
Inhibition of recombinant human full length His-tagged p110gamma expressed in baculovirus expression system measured after 60 mins in presence of ATP by ATP-competitive binding assay
|
Homo sapiens
|
27.4
nM
|
|
|
Inhibition of recombinant human full length His-tagged p110delta/p85alpha expressed in baculovirus expression system measured after 60 mins in presence of ATP by ATP-competitive binding assay
|
Homo sapiens
|
1.08
nM
|
|
|
Cytotoxicity against human MRC5 cells assessed as inhibition of cell viability at 20 uM measured after 48 hrs by MTT assay
|
Homo sapiens
|
18.41
%
|
|
|
Inhibition of PI3Kdelta (unknown origin) using PIP2 as substrate in presence of ATP measured after 60 mins by ADP-Glo assay
|
Homo sapiens
|
2.0
nM
|
|
