Anticancer potential of novel benzothiazolyl piperidine-3-carboxamide derivatives as CDKs and VEGFR2 multi-target kinase inhibitors

Abstract

The inhibition of cyclin-dependent kinases is a viable anticancer therapy due to their critical function in regulating cell cycle progression and transcription. The present study intended to design novel benzothiazolyl piperidine-3-carboxamide derivatives as multi-target CDKs and VEGFR2 inhibitor. Novel benzothiazolyl piperidine-3-carboxamide derivatives varying smaller and bulkier N-substitution at piperidine motif (4a–f) were designed based on the key structural features of SNS-032 (a CDK and VEGFR2 inhibitor). The compounds were subjected to extra-precision docking on seven CDKs and VEGFR2 kinase targets. The results revealed superior score/interaction of compounds with three CDKs (CDK2, CDK5, and CDK6) and VEGFR2, as compared to SNS-032. The best poses of 3, 4b, 4c and SNS-032 were used in WaterMap study to analyze the hydration sites. MD simulations (100 ns) in the TIP3P water model for 4c and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC–MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds 3 (IC₅₀ 0.026 µM) and 4c (IC₅₀ 0.048 µM) as compared to SNS-032 (IC₅₀ 0.052 µM) against CDK2, compounds 3 (IC₅₀ 0.315 µM), 4a (IC₅₀ 0.248 µM), 4b (IC₅₀ 0.276 µM), and 4c (IC₅₀ 0.338 µM) as compared to SNS-032 (IC₅₀ 0.476 µM) against CDK5, compounds 3 (IC₅₀ 0.221 µM), 4a (IC₅₀ 0.256 µM), 4b (IC₅₀ 0.282 µM), 4c (IC₅₀ 0.236 µM), and 4e (IC₅₀ 0.274 µM) as compared to SNS-032 (IC₅₀ 0.365 µM) against CDK6, and comparable potency of compound 4b (IC₅₀ 0.136 µM) with Sorafenib (IC₅₀ 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (3 and 4a–f) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity.

Graphical abstract