A novel series of N-(pyridin-2-yl)-4-(thiazol-5-yl)pyrimidin-2-amines as highly potent CDK4/6 inhibitors. (September 2017)

• Record Type: Journal Article
• Authors: Tadesse, Solomon; Zhu, Ge; Mekonnen, Laychiluh B; Lenjisa, Jimma L; Yu, Mingfeng; Brown, Michael P; Wang, Shudong
• Is Part Of: Future medicinal chemistry. Volume 9:Number 13(2017)
• Page Start: 1495
• Page End: 1506
• Publication Date: 2017-09
• Subjects: cancer -- CDK4/6 -- cell cycle -- drug development -- drug-resistance -- melanoma -- MV4–11 -- retinoblastoma -- targeted therapy; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2017-0076
• Languages: English
• ISSNs: 1756-8919

Abstract

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 of58 and69 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: Compounds58 and69 caused remarkable growth inhibition of melanoma cells, particularly the cells harboring multiple BRAF and NRAS mutations, via a CDK4/6-targeted mechanism of action.