Dataset Information

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.

ABSTRACT: Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

SUBMITTER: Cho YS

PROVIDER: S-EPMC4025827 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.

Cho Young Shin YS Angove Hayley H Brain Christopher C Chen Christine Hiu-Tung CH Cheng Hong H Cheng Robert R Chopra Rajiv R Chung Kristy K Congreve Miles M Dagostin Claudio C Davis Deborah J DJ Feltell Ruth R Giraldes John J Hiscock Steven D SD Kim Sunkyu S Kovats Steven S Lagu Bharat B Lewry Kim K Loo Alice A Lu Yipin Y Luzzio Michael M Maniara Wiesia W McMenamin Rachel R Mortenson Paul N PN Benning Rajdeep R O'Reilly Marc M Rees David C DC Shen Junqing J Smith Troy T Wang Yaping Y Williams Glyn G Woolford Alison J-A AJ Wrona Wojciech W Xu Mei M Yang Fan F Howard Steven S

ACS medicinal chemistry letters 20120517 6

Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model. ...[more]

PMID: 24900493

Dataset Information

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.

Publications

Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.
| S-EPMC4499826 | biostudies-literature

Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor.
| S-EPMC6900553 | biostudies-literature

Discovery of Imidazoisoindole Derivatives as Highly Potent and Orally Active Indoleamine-2,3-dioxygenase Inhibitors.
| S-EPMC6580535 | biostudies-literature

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1.
| S-EPMC7957935 | biostudies-literature

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists.
| S-EPMC4753552 | biostudies-literature

Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping.
| S-EPMC2664101 | biostudies-literature

Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors.
| S-EPMC6088353 | biostudies-literature

Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.
| S-EPMC4017972 | biostudies-other

Discovery of Orally Active Hydroxyethylamine Based SPPL2a Inhibitors.
| S-EPMC6580379 | biostudies-literature

Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor.
| S-EPMC11372460 | biostudies-literature