Design Synthesis and Evaluation of Novel Anti Cancer Agents Targeting Cyclin Dependent Kinase

Abstract

Cyclin-dependent kinases (CDKs) are involved in regulating the cell cycle and newlineare dysregulated in a variety of human cancers. Among various CDK types, inhibition of newlineCDK2, CDK4, and CDK6 represents a well-validated therapeutic strategy for the newlinedevelopment of targeted breast cancer agents. However, the emergence of drug resistance newlineand dose-limiting toxicities associated with currently available CDK inhibitors necessitates newlinethe discovery of new, selective, and less toxic inhibitors with optimal pharmacokinetic and newlinepharmacodynamic parameters. This study aims to design, synthesize, and evaluate novel newlinepyrazolo[3,4-d]pyrimidine derivatives and identify lead moieties as potential CDK2/4/6 newlineinhibitors. newlineThe study is divided into two distinct phases. In Phase I, a structure3activity newlinerelationship (SAR)-driven approach led to design a library of 40 novel pyrazolo[3,4- newlined]pyrimidine derivatives. From this series, 15 compounds (BK-01 to BK-15) were selected newlinebased on their binding affinity, followed by synthesized and characterized using IR, NMR, newlinemass spectrometry. All compounds followed Lipinski9s rule, indicating good oral newlinebioavailability. Among them, compound BK-11, bearing a trimethoxy-substituted newlinebenzylidene hydrazinyl moiety on the pyrazolo[3,4-d]pyrimidine scaffold, demonstrated the newlinemost potent cytotoxicity against the MCF-7 breast cancer cell line (IC¥ = 13.54 and#956;M). newlineMolecular docking studies revealed that BK-11 binds strongly to CDK2 (27.03 kcal/mol), newlineCDK4 (26.85 kcal/mol), and CDK6 (27.44 kcal/mol), outperforming standard inhibitors. newlineKey interactions with residues such as Lys 43 (CDK6), Ile 10 (CDK2), and Val 96 (CDK4) newlinewere observed newline