Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents

作者：Tadesse Solomon; Bantie Laychiluh; Tomusange Khamis; Yu Mingfeng; Islam Saiful; Bykovska Nataliya; Noll Benjamin; Zhu Ge; Li Peng; Lam Frankie; Kumarasiri Malika; Milne Robert; Wang Shudong^*

来源：British Journal of Pharmacology, 2018, 175(12): 2399-2413.

DOI：10.1111/bph.13974

BACKGROUND AND PURPOSE
Cyclin D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6.
EXPERIMENTAL APPROACH
The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F)-regulated gene expression and in vitro biopharmaceutical and in vivo pharmacokinetic profiling.
KEY RESULTS
We discovered several lead compounds that displayed >1000-fold selectivity for CDK4/6 over other members of the CDK family. The lead compounds, 82, 91 and 95, potently inhibited the growth of cancer cells by inducing G1 arrest with a concomitant reduction in the phosphorylation of Rb at S780 and in E2F-regulated gene expression. With a remarkable selectivity for CDK4 over 369 human protein kinases, 91 was identified as a highly potent and orally bioavailable drug candidate.
CONCLUSIONS AND IMPLICATIONS
We have identified unique and new inhibitors of CDK4/6 as potential drug candidates. Compound 91 represents an ideal candidate for further development as targeted cancer therapy.

• 出版日期2018-6