Ontology highlight
ABSTRACT:
SUBMITTER: Cho YS
PROVIDER: S-EPMC4025827 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
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]