Journal of Medicinal Chemistry p. 1892 - 1915 (2017)
Update date:2022-08-17
Topics:
Tadesse, Solomon
Yu, Mingfeng
Mekonnen, Laychiluh B.
Lam, Frankie
Islam, Saiful
Tomusange, Khamis
Rahaman, Muhammed H.
Noll, Benjamin
Basnet, Sunita K. C.
Teo, Theodosia
Albrecht, Hugo
Milne, Robert
Wang, Shudong
Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
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