A novel series of N-(pyridin-2-yl)-4-(thiazol-5-yl)pyrimidin-2-amines as highly potent CDK4/6 inhibitors

作者：Tadesse Solomon; Zhu Ge; Mekonnen Laychiluh B; Lenjisa Jimma L; Yu Mingfeng; Brown Michael P; Wang Shudong^*

来源：Future Medicinal Chemistry, 2017, 9(13): 1495-1506.

DOI：10.4155/fmc-2017-0076

• cancer
• CDK4/6
• cell cycle
• drug development
• drug-resistance
• melanoma
• MV4-11
• retinoblastoma
• targeted therapy

Aim: Inhibitors of CDK4/6 have emerged as a powerful class of therapeutics for treatment of several malignancies. We herein describe the identification of a new series of molecules that demonstrated excellent selectivity for CDK4/6 over CDKs1, 7 and 9. Results: Medicinal chemistry optimization led to the discovery of 58 and 69 that inhibited CDK4 and CDK4/6, respectively, with high potency and selectivity, and 58 and 69 exhibited potent antiproliferative activities in a panel of human cancer cell lines including leukemia, and cancers of the breast, colon, ovary, pancreas and prostate. Conclusion: Compounds 58 and 69 caused remarkable growth inhibition of melanoma cells, particularly the cells harboring multiple BRAF and NRAS mutations, via a CDK4/6-targeted mechanism of action.
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• 出版日期2017-9