期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 3, 期 6, 页码 445-449出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml200241a
关键词
CDK4/6; pRb phosphorylation; mantle cell lymphoma; fragment-based screening; structure-guided optimization
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.
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