|
Inhibition of aurora A kinase
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of aurora kinase inhibitors as anticancer agents.
Year : 2009
Volume : 52
Issue : 9
First Page : 2629
Last Page : 2651
Authors : Pollard JR, Mortimore M.
|
Inhibition of Lck
|
None
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of aurora kinase inhibitors as anticancer agents.
Year : 2009
Volume : 52
Issue : 9
First Page : 2629
Last Page : 2651
Authors : Pollard JR, Mortimore M.
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: LTK
|
None
|
398.11
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FRK
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: NTRK3
|
None
|
398.11
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RPS6KA3
|
None
|
794.33
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PLK4
|
None
|
39.81
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RET
|
None
|
398.11
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: LCK
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: STK6
|
None
|
0.5012
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: BTK
|
None
|
630.96
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FGFR1
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ROS1
|
None
|
158.49
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: BLK
|
None
|
39.81
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: EGFR
|
None
|
199.53
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: SRC
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ACK1
|
None
|
794.33
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ABL1
|
None
|
501.19
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: KDR
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: EPHA2
|
None
|
31.62
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PTK2
|
None
|
125.89
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: LRRK2
|
None
|
794.33
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: STK12
|
None
|
3.162
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FER
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PDPK1
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FLT1
|
None
|
794.33
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FGFR3
|
None
|
199.53
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PRKACA
|
None
|
630.96
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of recombinant Aurora B by radioactive flash plate assay
|
None
|
396.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.
Year : 2012
Volume : 55
Issue : 17
First Page : 7392
Last Page : 7416
Authors : Lawrence HR, Martin MP, Luo Y, Pireddu R, Yang H, Gevariya H, Ozcan S, Zhu JY, Kendig R, Rodriguez M, Elias R, Cheng JQ, Sebti SM, Schonbrunn E, Lawrence NJ.
Abstract : The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.
|
Inhibition of recombinant Aurora A by radioactive flash plate assay
|
None
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.
Year : 2012
Volume : 55
Issue : 17
First Page : 7392
Last Page : 7416
Authors : Lawrence HR, Martin MP, Luo Y, Pireddu R, Yang H, Gevariya H, Ozcan S, Zhu JY, Kendig R, Rodriguez M, Elias R, Cheng JQ, Sebti SM, Schonbrunn E, Lawrence NJ.
Abstract : The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.
|
Inhibition of aurora A (unknown origin)
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, quantum chemical studies and biological activity evaluation of pyrazole-benzimidazole derivatives as potent Aurora A/B kinase inhibitors.
Year : 2013
Volume : 23
Issue : 12
First Page : 3523
Last Page : 3530
Authors : Zheng Y, Zheng M, Ling X, Liu Y, Xue Y, An L, Gu N, Ji M.
Abstract : Novel pyrazole-benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence.
|
Inhibition of AURKA (unknown origin)
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Selectivity data: assessment, predictions, concordance, and implications.
Year : 2013
Volume : 56
Issue : 17
First Page : 6991
Last Page : 7002
Authors : Gao C, Cahya S, Nicolaou CA, Wang J, Watson IA, Cummins DJ, Iversen PW, Vieth M.
Abstract : Could high-quality in silico predictions in drug discovery eventually replace part or most of experimental testing? To evaluate the agreement of selectivity data from different experimental or predictive sources, we introduce the new metric concordance minimum significant ratio (cMSR). Empowered by cMSR, we find the overall level of agreement between predicted and experimental data to be comparable to that found between experimental results from different sources. However, for molecules that are either highly selective or potent, the concordance between different experimental sources is significantly higher than the concordance between experimental and predicted values. We also show that computational models built from one data set are less predictive for other data sources and highlight the importance of bias correction for assessing selectivity data. Finally, we show that small-molecule target space relationships derived from different data sources and predictive models share overall similarity but can significantly differ in details.
|
Inhibition of aurora A (unknown origin)
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR156497, an exquisitely selective inhibitor of aurora kinases.
Year : 2015
Volume : 58
Issue : 1
First Page : 362
Last Page : 375
Authors : Carry JC, Clerc F, Minoux H, Schio L, Mauger J, Nair A, Parmantier E, Le Moigne R, Delorme C, Nicolas JP, Krick A, Abécassis PY, Crocq-Stuerga V, Pouzieux S, Delarbre L, Maignan S, Bertrand T, Bjergarde K, Ma N, Lachaud S, Guizani H, Lebel R, Doerflinger G, Monget S, Perron S, Gasse F, Angouillant-Boniface O, Filoche-Rommé B, Murer M, Gontier S, Prévost C, Monteiro ML, Combeau C.
Abstract : The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
|
Inhibition of aurora B (unknown origin)
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR156497, an exquisitely selective inhibitor of aurora kinases.
Year : 2015
Volume : 58
Issue : 1
First Page : 362
Last Page : 375
Authors : Carry JC, Clerc F, Minoux H, Schio L, Mauger J, Nair A, Parmantier E, Le Moigne R, Delorme C, Nicolas JP, Krick A, Abécassis PY, Crocq-Stuerga V, Pouzieux S, Delarbre L, Maignan S, Bertrand T, Bjergarde K, Ma N, Lachaud S, Guizani H, Lebel R, Doerflinger G, Monget S, Perron S, Gasse F, Angouillant-Boniface O, Filoche-Rommé B, Murer M, Gontier S, Prévost C, Monteiro ML, Combeau C.
Abstract : The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
|
Antiproliferative activity against human NCI-H358 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human LU99A cells after 72 hrs by WST8 assay
|
Homo sapiens
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human Lu116 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
97.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human LC2/ad cells after 72 hrs by WST8 assay
|
Homo sapiens
|
77.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human PC14 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human HCT15 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
740.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human HCT116 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
95.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human HT-29 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human MIAPaCa2 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human GSS cells after 72 hrs by WST8 assay
|
Homo sapiens
|
39.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human MKN45 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
93.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Antiproliferative activity against human HL60 cells after 72 hrs by WST8 assay
|
Homo sapiens
|
74.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
Year : 2015
Volume : 58
Issue : 4
First Page : 1760
Last Page : 1775
Authors : Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
Abstract : Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
|
Inhibition of recombinant mouse aurora kinase A expressed in insect Sf9 cells using biotin-GLRRASLG as substrate in presence of [gamma-33P]ATP
|
Mus musculus
|
1.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors.
Year : 2015
Volume : 6
Issue : 6
First Page : 630
Last Page : 634
Authors : Sells TB, Chau R, Ecsedy JA, Gershman RE, Hoar K, Huck J, Janowick DA, Kadambi VJ, LeRoy PJ, Stirling M, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Balani SK, Bolen JB, Manfredi MG, Claiborne CF.
Abstract : The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.
|
Inhibition of aurora kinase A autophosphorylation at T288 in human HCT116 cells by immunofluorescence analysis
|
Homo sapiens
|
7.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors.
Year : 2015
Volume : 6
Issue : 6
First Page : 630
Last Page : 634
Authors : Sells TB, Chau R, Ecsedy JA, Gershman RE, Hoar K, Huck J, Janowick DA, Kadambi VJ, LeRoy PJ, Stirling M, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Balani SK, Bolen JB, Manfredi MG, Claiborne CF.
Abstract : The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.
|
Competitive inhibition of recombinant mouse aurora kinase A expressed in insect Sf9 cells in presence of ATP
|
Mus musculus
|
0.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors.
Year : 2015
Volume : 6
Issue : 6
First Page : 630
Last Page : 634
Authors : Sells TB, Chau R, Ecsedy JA, Gershman RE, Hoar K, Huck J, Janowick DA, Kadambi VJ, LeRoy PJ, Stirling M, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Balani SK, Bolen JB, Manfredi MG, Claiborne CF.
Abstract : The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.
|
Binding affinity to GABAA alpha-1 benzodiazepine binding site (unknown origin)
|
Homo sapiens
|
490.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors.
Year : 2015
Volume : 6
Issue : 6
First Page : 630
Last Page : 634
Authors : Sells TB, Chau R, Ecsedy JA, Gershman RE, Hoar K, Huck J, Janowick DA, Kadambi VJ, LeRoy PJ, Stirling M, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Balani SK, Bolen JB, Manfredi MG, Claiborne CF.
Abstract : The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.
|
Inhibition of His-tagged human Aurora A kinase (122 to 40 residues) expressed in Escherichia coli BL21 (DE3) Rosetta cells using biotinylated STK2 substrate incubated for 30 mins by HTRF assay
|
Homo sapiens
|
0.04
nM
|
|
Journal : J Med Chem
Title : Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
Year : 2016
Volume : 59
Issue : 15
First Page : 7188
Last Page : 7211
Authors : Kilchmann F, Marcaida MJ, Kotak S, Schick T, Boss SD, Awale M, Gönczy P, Reymond JL.
Abstract : Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
|
Inhibition of Aurora-B/INCENP (unknown origin) using biotinylated STK2 substrate incubated for 30 mins by HTRF assay
|
Homo sapiens
|
1.1
nM
|
|
Journal : J Med Chem
Title : Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
Year : 2016
Volume : 59
Issue : 15
First Page : 7188
Last Page : 7211
Authors : Kilchmann F, Marcaida MJ, Kotak S, Schick T, Boss SD, Awale M, Gönczy P, Reymond JL.
Abstract : Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
|
Inhibition of Aurora A kinase autophosphorylation at Thr288 in human HeLa Kyoto cells incubated for 20 hrs
|
Homo sapiens
|
6.7
nM
|
|
Journal : J Med Chem
Title : Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
Year : 2016
Volume : 59
Issue : 15
First Page : 7188
Last Page : 7211
Authors : Kilchmann F, Marcaida MJ, Kotak S, Schick T, Boss SD, Awale M, Gönczy P, Reymond JL.
Abstract : Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
|
Inhibition of Aurora B kinase in human HeLa Kyoto cells assessed as effect on distribution of phspho-histone H3 ser10 level incubated for 20 hrs
|
Homo sapiens
|
1.5
nM
|
|
Journal : J Med Chem
Title : Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
Year : 2016
Volume : 59
Issue : 15
First Page : 7188
Last Page : 7211
Authors : Kilchmann F, Marcaida MJ, Kotak S, Schick T, Boss SD, Awale M, Gönczy P, Reymond JL.
Abstract : Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
|
Kinase Assay: For in vitro method for measuring the inhibitory activity of the aforementioned compounds on the aurora A kinase activity was carried out referring to the method described in JP-A-2008-81492. As the first step of measuring the inhibitory activity of the compound, the test compound was serially diluted with dimethyl sulfoxide (DMSO). Subsequently, purified human aurora A protein, FL-Peptide 21 (Caliper Life Sciences, Inc., a final concentration of 100 nM), ATP (a final concentration of 5 μM), and the solution of the compound of the present invention in DMSO (a final DMSO concentration of 5%) were added to a reaction buffer [50 mM Tris-hydrochloric acid buffer (pH 7.4), 15 mM magnesium acetate, and 0.2 mM ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA)]. Then, the resulting mixture was incubated at 25° C. for 50 minutes to carry out kinase reactions. Then, the IMAP® Progressive Binding Reagent diluted 500-fold with the IMAP® Progressive Binding Buffer A (the product of Molecular Devices, LLC.) was added thereto to terminate the kinase reaction. After leaving the resulting product to stand in the dark at room temperature for 120 minutes, the amount of phosphorylation was determined from the degree of fluorescence polarization as measured by the PHERAstar (BMG LABTECH, excitation wavelength of 485 nm, detection wavelength of 520 nm).
|
Homo sapiens
|
0.6
nM
|
|
Title : Piperidine compound or salt thereof
Year : 2016
|
Kinase Assay: The in vitro method for measuring the inhibitory activity of the test compound on the aurora B kinase activity was performed in a similar manner as the above method for aurora A, and purified recombinant human aurora B protein was purchased from Carna Biosciences, Inc. The reaction buffer has the following composition: 20 mM HEPES (pH 7.4), 2 mM DTT, 0.01% Tween-20, magnesium chloride at a final concentration of 1 mM, and ATP at a final concentration of 40 μM, and the incubation time was 60 minutes.
|
Homo sapiens
|
90.0
nM
|
|
Title : Piperidine compound or salt thereof
Year : 2016
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
78.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
5.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
195.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
962.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
309.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
455.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
184.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
629.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
289.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Inhibition of Aurora A kinase (unknown origin)
|
Homo sapiens
|
1.2
nM
|
|
Journal : Eur J Med Chem
Title : A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies.
Year : 2017
Volume : 140
First Page : 1
Last Page : 19
Authors : Borisa AC, Bhatt HG.
Abstract : Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc. IC50 values of tumor growth inhibition, in-vitro and in-vivo activity along with clinical trial data. Here, we took efforts to describe essence of Aurora kinase and its inhibition which could be used to develop anti-mitotic drug for the treatment of cancer. In conclusion, we also discuss future perspectives for development of novel inhibitors and their scope in drug development process.
|
Inhibition of recombinant aurora B (unknown origin)
|
Homo sapiens
|
396.5
nM
|
|
Journal : Eur J Med Chem
Title : A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies.
Year : 2017
Volume : 140
First Page : 1
Last Page : 19
Authors : Borisa AC, Bhatt HG.
Abstract : Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc. IC50 values of tumor growth inhibition, in-vitro and in-vivo activity along with clinical trial data. Here, we took efforts to describe essence of Aurora kinase and its inhibition which could be used to develop anti-mitotic drug for the treatment of cancer. In conclusion, we also discuss future perspectives for development of novel inhibitors and their scope in drug development process.
|
Suppression of cell mitosis in human multiple myeloma cells
|
Homo sapiens
|
3.0
nM
|
|
Journal : Eur J Med Chem
Title : A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies.
Year : 2017
Volume : 140
First Page : 1
Last Page : 19
Authors : Borisa AC, Bhatt HG.
Abstract : Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc. IC50 values of tumor growth inhibition, in-vitro and in-vivo activity along with clinical trial data. Here, we took efforts to describe essence of Aurora kinase and its inhibition which could be used to develop anti-mitotic drug for the treatment of cancer. In conclusion, we also discuss future perspectives for development of novel inhibitors and their scope in drug development process.
|
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
|
24.63
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of Aurora A (unknown origin)
|
Homo sapiens
|
1.2
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and identification of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl as potential Aurora A inhibitors.
Year : 2019
Volume : 27
Issue : 1
First Page : 65
Last Page : 78
Authors : Sang CY, Qin WW, Zhang XJ, Xu Y, Ma YZ, Wang XR, Hui L, Chen SW.
Abstract : The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.02
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
0.8165
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.23
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.14
%
|
|
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
|
-0.14
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.23
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of recombinant Aurora A (unknown origin) by radioactive flashplate assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors.
Year : 2020
Volume : 28
Issue : 5
First Page : 115351
Last Page : 115351
Authors : Bo YX, Xiang R, Xu Y, Hao SY, Wang XR, Chen SW.
Abstract : Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC<sub>50</sub> values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC<sub>50</sub> values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
|
Inhibition of Aurora A (unknown origin)
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : Monomeric Targeted Protein Degraders.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11330
Last Page : 11361
Authors : Hanan EJ,Liang J,Wang X,Blake RA,Blaquiere N,Staben ST
Abstract : The discovery and development of targeted protein degraders have become important areas of research in the field of medicinal chemistry. Inducing degradation of a target protein presents several advantages relative to simple inhibition including a potential for extended duration of action and more profound pharmacology. While engineered heterodimeric molecules have recently been a major focus within industry and academia, this Perspective highlights examples of targeted protein degradation observed for smaller, monomeric molecules. Methods and tools for evaluating protein degradation as well as a discussion of physical properties of monomeric vs engineered heterodimeric degraders are presented.
|
Antiproliferative activity against human SK-N-BE2 cells after 72 hrs by CyQUANT reagent based assay
|
Homo sapiens
|
40.89
nM
|
|
Journal : J Med Chem
Title : Monomeric Targeted Protein Degraders.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11330
Last Page : 11361
Authors : Hanan EJ,Liang J,Wang X,Blake RA,Blaquiere N,Staben ST
Abstract : The discovery and development of targeted protein degraders have become important areas of research in the field of medicinal chemistry. Inducing degradation of a target protein presents several advantages relative to simple inhibition including a potential for extended duration of action and more profound pharmacology. While engineered heterodimeric molecules have recently been a major focus within industry and academia, this Perspective highlights examples of targeted protein degradation observed for smaller, monomeric molecules. Methods and tools for evaluating protein degradation as well as a discussion of physical properties of monomeric vs engineered heterodimeric degraders are presented.
|
Inhibition of recombinant GST-tagged N-terminal truncated human Aurora A (123 to 401 residues) expressed in Sf9 insect cell using tetra-LRRASLG peptide as substrate incubated for 20 mins by Kinase-Glo plus luminescent kinase assay
|
Homo sapiens
|
13.3
nM
|
|
|
Inhibition of Histone H3 phosphorylation in human NCI-H82 cells xenografted in assessed as reduction in phosphorylation at Ser 10 residue at 100 mg/kg, po measured upto 8 hrs by western blot analysis relative to control
|
Homo sapiens
|
90.0
%
|
|
