| Abstract
| - The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Sincederegulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibitionof CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer.The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitiveinhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with asubstituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position hasbeen identified as the critical structure responsible for the CDK inhibitory activity. Further optimization hasled to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4but are inactive against a large panel of serine/threonine and tyrosine kinases (Ki> 10 μM). As one of theserepresentative analogues, compound 39 (R547) has the best CDK inhibitory activities (Ki = 0.001, 0.003,and 0.001 μM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibitingthe growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 μM). An X-raycrystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that isconsistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 humancolorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of itssuperior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trialfor the treatment of cancer.
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