2. Academic Validation
  3. Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation

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

  • J Med Chem. 2017 Mar 9;60(5):1892-1915. doi: 10.1021/acs.jmedchem.6b01670.
Solomon Tadesse 1,  Mingfeng Yu 1,  Laychiluh B Mekonnen 1,  Frankie Lam 1,  Saiful Islam 1,  Khamis Tomusange 1,  Muhammed H Rahaman 1,  Benjamin Noll 1,  Sunita K C Basnet 1,  Theodosia Teo 1,  Hugo Albrecht 1,  Robert Milne 1,  Shudong Wang 1
Affiliations

Affiliation

  • 1 Center for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Center for Cancer Biology, University of South Australia , Adelaide, South Australia 5001, Australia.
PMID: 28156111 DOI: 10.1021/acs.jmedchem.6b01670
Abstract

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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