Cinnamamide-Chalcone Derivatives as CDK2 Inhibitors: Synthesis, Pharmacological Evaluation, and Molecular Modelling Study

Abstract A series of 13 novel cinnamamide-chalcone derivatives (2a-2m) were synthesized and evaluated for their antiproliferative activity against MCF-7, K562, U373MG, and HT-29 cell lines by SRB assay. Considering the activities on MCF-7 cell line, eight compounds were tested for the in-vitro CDK2 inhibition and four (2g, 2h, 2k and 2l) were found to possess good activity (IC50<10µM). These four compounds were tested on EGFR kinase to assess the selectivity towards CDK2 and were found be nearly two times more selective. To corroborate the in-vitro enzyme assay data with binding, the compounds were docked into the CDK2 and EGFR using Glide software. The docking studies reveal that all eight compounds form hydrogen bonds with Lys33 (β-3 region) and Leu83 (hinge region) in CDK2 and the docking scores correlate well with the IC50 values. The most active compounds on CDK2 when docked in EGFR had lower docking scores. Only one compound interacts with Lys721 (β-3 region) and Met769 (hinge region). The stability of interactions with CDK2 was assessed for 2k and 2l by molecular dynamics simulation using Desmond software. In conclusion, three compounds possess excellent activity against MCF-7 cell line and good activity against CDK2.