Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

Purines and their derivatives, modified at C-2 with 4′-sulfamoylanilino and at C-6 with various groups, were synthesized to target selective binding to CDK2 over CDK1. 6-Substituted variants favoring competitive inhibition at CDK2′s ATP binding site were identified, showing 10-80-fold higher inhibition of CDK2 compared to CDK1. Particularly notable was compound 73, 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide, which demonstrated potent activity against CDK2 (IC50 0.044 μM) while being significantly CDK2-IN-73 less active against CDK1 (IC50 86 μM), making it a valuable tool for studying cell cycle regulation. Crystallographic studies of inhibitor-kinase complexes revealed that the inhibitor stabilizes a glycine-rich loop conformation crucial for shaping the ATP ribose binding pocket, a feature preferred in CDK2 but absent in CDK1. This structural insight suggests potential for designing inhibitors that selectively target CDK2 over CDK1.