1 research outputs found
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)Âpyrimidin-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