|
GSK_TCMDC: Inhibition of Plasmodium falciparum 3D7 in whole red blood cells, using parasite LDH activity as an index of growth. Test compounds present at 2uM
|
Plasmodium falciparum
|
99.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum Dd2 in whole red blood cells, using parasite LDH activity as an index of growth. Test compounds present at 2uM
|
Plasmodium falciparum
|
99.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum 3D7 LDH activity, using an LDH reporter assay. Test compounds present at 2uM
|
Plasmodium falciparum
|
0.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Percent inhibition of human HepG2 cell line. Test compounds present at 10uM.
|
Homo sapiens
|
47.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
Inhibition of rat brain mTOR assessed as p70S6K-GST protein phosphorylation after 30 mins by ELISA
|
Rattus norvegicus
|
45.0
nM
|
|
|
Inhibition of PI3K assessed as PIP3 level after 20 mins by HTRF assay
|
None
|
6.5
nM
|
|
|
Antiproliferative activity against human LNCAP cells after 3 days by MTS assay
|
Homo sapiens
|
210.0
nM
|
|
|
Inhibition of p110alpha
|
None
|
16.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
Year : 2010
Volume : 6
Issue : 2
First Page : 117
Last Page : 124
Authors : Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C, Gaillard P, Rückle T, Schwarz MK, Shokat KM, Shaw JP, Williams RL.
Abstract : Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
|
Inhibition of p110beta
|
None
|
44.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
Year : 2010
Volume : 6
Issue : 2
First Page : 117
Last Page : 124
Authors : Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C, Gaillard P, Rückle T, Schwarz MK, Shokat KM, Shaw JP, Williams RL.
Abstract : Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
|
Inhibition of p110gamma
|
None
|
49.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
Year : 2010
Volume : 6
Issue : 2
First Page : 117
Last Page : 124
Authors : Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C, Gaillard P, Rückle T, Schwarz MK, Shokat KM, Shaw JP, Williams RL.
Abstract : Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
|
Inhibition of p110delta
|
None
|
4.6
nM
|
|
Journal : Nat. Chem. Biol.
Title : The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
Year : 2010
Volume : 6
Issue : 2
First Page : 117
Last Page : 124
Authors : Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C, Gaillard P, Rückle T, Schwarz MK, Shokat KM, Shaw JP, Williams RL.
Abstract : Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
|
Inhibition of PIK3CA H1047R mutant-mediated cell signaling in human HCT116 cells expressing PTEN assessed as inhibition of insulin-induced pAkt/PKB phosphorylation at Thr308 treated for 15 mins before insulin challenge measured after 5 mins by immunoblotting
|
Homo sapiens
|
78.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of PIK3CA H1047R mutant-mediated cell signaling in human HCT116 cells expressing PTEN assessed as inhibition of insulin-induced pAkt/PKB phosphorylation at Ser473 treated for 15 mins before insulin challenge measured after 5 mins by immunoblotting
|
Homo sapiens
|
97.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of PIK3CA-mediated cell signaling in PTEN-deficient human U87MG cells assessed as inhibition of insulin-induced pAkt/PKB phosphorylation at Thr308 treated for 15 mins before insulin challenge measured after 5 mins by immunoblotting
|
Homo sapiens
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of PIK3CA-mediated cell signaling in PTEN-deficient human U87MG cells assessed as inhibition of insulin-induced pAkt/PKB phosphorylation at Ser473 treated for 15 mins before insulin challenge measured after 5 mins by immunoblotting
|
Homo sapiens
|
111.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human PI3K p110alpha helical domain E545K mutant after 2 hrs by HTRF assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human His-tagged PI3K p110alpha H1047R mutant after 2 hrs by HTRF assay
|
Homo sapiens
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human His-tagged PI3K p110gamma after 2 hrs by HTRF assay
|
Homo sapiens
|
83.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human His-tagged PI3K p110delta after 2 hrs by HTRF assay
|
Homo sapiens
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human His-tagged PI3K p110beta after 2 hrs by HTRF assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human His-tagged PI3K p110alpha after 2 hrs by HTRF assay
|
Homo sapiens
|
8.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Antiproliferative activity against human NZOV9 cells expressing p110alpha kinase Y1021C mutant assessed as incorporation of [3H]thymidine after 5 days
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Antiproliferative activity against human NZB5 cells expressing wild type p110alpha assessed as incorporation of [3H]thymidine after 5 days
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of bovine recombinant PI3K p110delta expressed in Sf21 insect cells using phosphatidylinositol as substrate after 1 hr by phosphoimaging
|
Bos taurus
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of human recombinant PI3K p110beta expressed in Sf21 insect cells using phosphatidylinositol as substrate after 1 hr by phosphoimaging
|
Homo sapiens
|
4.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of mouse recombinant PI3K p110alpha expressed in Sf21 insect cells using phosphatidylinositol as substrate after 1 hr by phosphoimaging
|
Mus musculus
|
8.6
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
Year : 2011
Volume : 54
Issue : 20
First Page : 7105
Last Page : 7126
Authors : Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR.
Abstract : A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
|
Inhibition of mTOR
|
None
|
350.0
nM
|
|
|
Inhibition of PI3Kalpha
|
None
|
26.0
nM
|
|
|
Inhibition of recombinant PI3Kalpha by HTRF assay
|
None
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs.
Year : 2012
Volume : 20
Issue : 6
First Page : 1947
Last Page : 1951
Authors : Kong D, Yamori T.
Abstract : Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates.
|
Inhibition of recombinant PI3Kbeta HTRF assay
|
None
|
44.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs.
Year : 2012
Volume : 20
Issue : 6
First Page : 1947
Last Page : 1951
Authors : Kong D, Yamori T.
Abstract : Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates.
|
Inhibition of recombinant PI3Kgamma HTRF assay
|
None
|
49.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs.
Year : 2012
Volume : 20
Issue : 6
First Page : 1947
Last Page : 1951
Authors : Kong D, Yamori T.
Abstract : Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates.
|
Inhibition of recombinant PI3Kdelta HTRF assay
|
None
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs.
Year : 2012
Volume : 20
Issue : 6
First Page : 1947
Last Page : 1951
Authors : Kong D, Yamori T.
Abstract : Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates.
|
Inhibition of PI3Kdelta
|
None
|
4.6
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 (unknown origin) expressed in SF21 cells using phosphatidylinositol as substrate after 60 mins by Kinase-Glo assay
|
Homo sapiens
|
3.0
nM
|
|
|
Inhibition of PI3Kgamma (unknown origin) expressed in SF21 cells using phosphatidylinositol as substrate after 60 mins by Kinase-Glo assay
|
Homo sapiens
|
38.0
nM
|
|
|
Inhibition of PI3Kbeta (unknown origin) expressed in SF21 cells using phosphatidylinositol as substrate after 60 mins by Kinase-Glo assay
|
Homo sapiens
|
6.0
nM
|
|
|
Inhibition of PI3Kalpha (unknown origin) expressed in SF21 cells using phosphatidylinositol as substrate after 60 mins by Kinase-Glo assay
|
Homo sapiens
|
6.0
nM
|
|
|
Inhibition of PI3K-delta (unknown origin) assessed as decrease in ATP consumption using phosphatidylinositol bisphosphate and 10 uM ATP as substrate measured after 60 mins by luminescence assay
|
Homo sapiens
|
3.0
nM
|
|
|
Inhibition of PI3K-gamma (unknown origin) assessed as decrease in ATP consumption using phosphatidylinositol bisphosphate and 10 uM ATP as substrate measured after 60 mins by luminescence assay
|
Homo sapiens
|
38.0
nM
|
|
|
Inhibition of PI3K-beta (unknown origin) assessed as decrease in ATP consumption using phosphatidylinositol bisphosphate and 10 uM ATP as substrate measured after 60 mins by luminescence assay
|
Homo sapiens
|
6.0
nM
|
|
|
Inhibition of PI3K-alpha (unknown origin) assessed as decrease in ATP consumption using phosphatidylinositol bisphosphate and 10 uM ATP as substrate measured after 60 mins by luminescence assay
|
Homo sapiens
|
6.0
nM
|
|
|
Inhibition of PI3Kbeta (unknown origin)
|
Homo sapiens
|
44.0
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
|
16.0
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
|
49.0
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
|
5.0
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 human PI3KC2beta by non-radiometric ADP-Glo assay
|
Homo sapiens
|
180.0
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 human PI3KCdelta by non-radiometric ADP-Glo assay
|
Homo sapiens
|
6.0
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 human mTOR by non-radiometric ADP-Glo assay
|
Homo sapiens
|
370.0
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 PI3K p110alpha (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring.
Year : 2015
Volume : 58
Issue : 1
First Page : 41
Last Page : 71
Authors : Andrs M, Korabecny J, Jun D, Hodny Z, Bartek J, Kuca K.
Abstract : Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.
|
Inhibition of PI3K p110beta (unknown origin)
|
Homo sapiens
|
44.0
nM
|
|
Journal : J. Med. Chem.
Title : Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring.
Year : 2015
Volume : 58
Issue : 1
First Page : 41
Last Page : 71
Authors : Andrs M, Korabecny J, Jun D, Hodny Z, Bartek J, Kuca K.
Abstract : Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.
|
Inhibition of PI3K p110gamma (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring.
Year : 2015
Volume : 58
Issue : 1
First Page : 41
Last Page : 71
Authors : Andrs M, Korabecny J, Jun D, Hodny Z, Bartek J, Kuca K.
Abstract : Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.
|
Inhibition of PI3K p110delta (unknown origin)
|
Homo sapiens
|
49.0
nM
|
|
Journal : J. Med. Chem.
Title : Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring.
Year : 2015
Volume : 58
Issue : 1
First Page : 41
Last Page : 71
Authors : Andrs M, Korabecny J, Jun D, Hodny Z, Bartek J, Kuca K.
Abstract : Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.
|
ST_JUDE_LEISH: Cytotoxicity at 2uM final concentration against transgenic Leishmania Mexicana promastigotes LmGLUT1 that are glucose transport deficient and complemented with the human glucose transporter GLUT1. Activity is measured by DNA content using SYBR green in vitro
|
Leishmania mexicana
|
2.11
%
|
|
Title : St. Jude Leishmania screening dataset.
|
ST_JUDE_LEISH: Cytotoxicity at 2uM final concentration against transgenic Leishmania Mexicana promastigotes LmPfHT that are glucose transport deficient and complemented with the Plasmodium falciparum hexose transporter. Activity is measured by by DNA content using SYBR green in vitro
|
Leishmania mexicana
|
2.9
%
|
|
Title : St. Jude Leishmania screening dataset.
|
ST_JUDE_LEISH: Cytotoxicity at 2uM final concentration against transgenic Leishmania Mexicana promastigotes LmGT2 that are glucose transport deficient and complemented with the L. Mexicana glucose transporter 2. Activity is measured by by DNA content using SYBR green in vitro
|
Leishmania mexicana
|
3.12
%
|
|
Title : St. Jude Leishmania screening dataset.
|
Inhibition of human recombinant PI3KC2beta using substrate PI incubated for 1 hr by Adapta kinase assay
|
Homo sapiens
|
180.0
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.
|
Inhibition of his-tagged human recombinant PIK3CD/PIK3R1 using substrate PI incubated for 1 hr by Adapta kinase assay
|
Homo sapiens
|
6.0
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.
|
Inhibition of human recombinant mTOR using substrate PI incubated for 1 hr by Adapta kinase assay
|
Homo sapiens
|
370.0
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.
|
Inhibition of PI3Kbeta (unknown origin) expressed in Escherichia coli-infected fall armyworm sf21 cells co-expressing p85 by kinase-glo luminescence assay
|
Homo sapiens
|
6.0
nM
|
|
|
Inhibition of recombinant human full length His-tagged PI3K p110alpha/p85alpha expressed in baculovirus expression system coexpressing PIK3R1 by TR-FRET assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).
Year : 2017
Volume : 8
Issue : 8
First Page : 808
Last Page : 813
Authors : Van Dort ME, Galbán S, Nino CA, Hong H, Apfelbaum AA, Luker GD, Thurber GM, Atangcho L, Besirli CG, Ross BD.
Abstract : The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.
|
Inhibition of PI3Kbeta (unknown origin) by TR-FRET assay
|
Homo sapiens
|
15.2
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).
Year : 2017
Volume : 8
Issue : 8
First Page : 808
Last Page : 813
Authors : Van Dort ME, Galbán S, Nino CA, Hong H, Apfelbaum AA, Luker GD, Thurber GM, Atangcho L, Besirli CG, Ross BD.
Abstract : The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.
|
Inhibition of recombinant human full length His-tagged PI3K p110gamma expressed in baculovirus expression system by TR-FRET assay
|
Homo sapiens
|
20.8
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).
Year : 2017
Volume : 8
Issue : 8
First Page : 808
Last Page : 813
Authors : Van Dort ME, Galbán S, Nino CA, Hong H, Apfelbaum AA, Luker GD, Thurber GM, Atangcho L, Besirli CG, Ross BD.
Abstract : The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.
|
Inhibition of recombinant human full length His-tagged PI3K p110delta/p85alpha expressed in baculovirus expression system coexpressing PIK3R1 by TR-FRET assay
|
Homo sapiens
|
3.9
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).
Year : 2017
Volume : 8
Issue : 8
First Page : 808
Last Page : 813
Authors : Van Dort ME, Galbán S, Nino CA, Hong H, Apfelbaum AA, Luker GD, Thurber GM, Atangcho L, Besirli CG, Ross BD.
Abstract : The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.
|
Inhibition of PI3Kalpha (unknown origin) using PIP2 as substrate after 1 hr by Kinase-Glo luminescent kinase assay
|
Homo sapiens
|
16.0
nM
|
|
|
Inhibition of PI3Kalpha H1047R mutant (unknown origin) by HTRF assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors.
Year : 2018
Volume : 158
First Page : 707
Last Page : 719
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC50 = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.
|
Inhibition of wild type PI3Kalpha (unknown origin) after 40 mins by kinase-Glo reagent based luminescence assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors.
Year : 2018
Volume : 158
First Page : 707
Last Page : 719
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC50 = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.
|
Inhibition of PI3Kbeta (unknown origin) after 40 mins by kinase-Glo reagent based luminescence assay
|
Homo sapiens
|
44.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors.
Year : 2018
Volume : 158
First Page : 707
Last Page : 719
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC50 = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.
|
Inhibition of PI3Kgamma (unknown origin) after 40 mins by kinase-Glo reagent based luminescence assay
|
Homo sapiens
|
51.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors.
Year : 2018
Volume : 158
First Page : 707
Last Page : 719
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC50 = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.
|
Inhibition of PI3Kdelta (unknown origin) after 40 mins by kinase-Glo reagent based luminescence assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kα H1047R mutant inhibitors.
Year : 2018
Volume : 158
First Page : 707
Last Page : 719
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC50 = 115.3 μM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.55 μM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kα H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 μM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kα inhibitor.
|
Inhibition of PI3K p110gamma/p85alpha (unknown origin) assessed as reduction in PIP2 to PIP3 conversion by HTRF assay
|
Homo sapiens
|
4.6
nM
|
|
Journal : Eur J Med Chem
Title : 1,3,5-Triazines: A promising scaffold for anticancer drugs development.
Year : 2017
Volume : 142
First Page : 523
Last Page : 549
Authors : Cascioferro S, Parrino B, Spanò V, Carbone A, Montalbano A, Barraja P, Diana P, Cirrincione G.
Abstract : This review covering literature reports from the beginning of this century to 2016 describes the synthetic pathways, the antitumor activity, the structure-activity relationship and, whenever reported, the possible mechanism of action of 1,3,5-triazine derivatives as well as of their hetero-fused compounds. Many 1,3,5-triazine derivatives, both uncondensed and hetero-fused, have shown remarkable antitumor activities and some of them reached clinical development.
|
Inhibition of recombinant full length PI3K p85alpha/p110alpha H1047R mutant (unknown origin) expressed in baculovirus infected sf9 cells using PIP2 as substrate preincubated for 10 mins followed by ATP addition and measured after 45 mins by HTRF assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship.
Year : 2018
Volume : 157
First Page : 37
Last Page : 49
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Tang Q, Hu P, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.
|
Inhibition of recombinant full length PI3K p110alpha/p85alpha (unknown origin) expressed in baculovirus infected sf9 cells using PIP2 as substrate preincubated for 10 mins followed by ATP addition and measured after 45 mins by HTRF assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship.
Year : 2018
Volume : 157
First Page : 37
Last Page : 49
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Tang Q, Hu P, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.
|
Inhibition of PI3K-beta (unknown origin) after 40 mins by Kinase-Glo assay
|
Homo sapiens
|
44.0
nM
|
|
Journal : Eur J Med Chem
Title : Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship.
Year : 2018
Volume : 157
First Page : 37
Last Page : 49
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Tang Q, Hu P, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.
|
Inhibition of PI3K-gamma (unknown origin) after 40 mins by Kinase-Glo assay
|
Homo sapiens
|
51.0
nM
|
|
Journal : Eur J Med Chem
Title : Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship.
Year : 2018
Volume : 157
First Page : 37
Last Page : 49
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Tang Q, Hu P, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.
|
Inhibition of PI3K-delta (unknown origin) after 40 mins by Kinase-Glo assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship.
Year : 2018
Volume : 157
First Page : 37
Last Page : 49
Authors : Zhang N, Yu Z, Yang X, Zhou Y, Tang Q, Hu P, Wang J, Zhang SL, Wang MW, He Y.
Abstract : Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up-regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.
|
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
|
90.88
%
|
|
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.
|
Competitive inhibition of PI3Kalpha (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Competitive inhibition of PI3Kbeta (unknown origin)
|
Homo sapiens
|
44.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Competitive inhibition of PI3Kdelta (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
Competitive inhibition of PI3Kgamma (unknown origin)
|
Homo sapiens
|
49.0
nM
|
|
Journal : Eur J Med Chem
Title : Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer.
Year : 2019
Volume : 183
First Page : 111718
Last Page : 111718
Authors : Elmenier FM, Lasheen DS, Abouzid KAM.
Abstract : Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
7.52
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.614
%
|
|
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.
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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
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Chlorocebus sabaeus
|
0.59
%
|
|
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
|
5.36
%
|
|
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
|
5.36
%
|
|
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
|
0.59
%
|
|
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.
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Inhibition of human PI3Kalpha by TR-FRET based Adapta assay
|
Homo sapiens
|
5.0
nM
|
|
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Inhibition of human PI3Kbeta by TR-FRET based Adapta assay
|
Homo sapiens
|
15.2
nM
|
|
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Inhibition of human PI3Kgamma by TR-FRET based Adapta assay
|
Homo sapiens
|
20.8
nM
|
|
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Inhibition of human PI3Kdelta by TR-FRET based Adapta assay
|
Homo sapiens
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3.9
nM
|
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