Highly Potent, Selective, and Orally Bioavailable 4‑Thiazol‑<i>N</i>‑(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation

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-<i>N</i>-(pyridin-2-yl)­pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in <b>83</b>, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of <b>83</b> 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 <b>83</b> as a clinical development candidate