Cinnamamide-chalcone derivatives as CDK2 inhibitors: synthesis, pharmacological evaluation, and molecular modelling study

Abstract

Thirteen novel cinnamamide-chalcone derivatives were synthesized and tested for their antiproliferative activity against MCF-7, K562, U-373MG, and HT-29 cell lines using SRB assay. Eight compounds were tested for the in vitro CDK2 inhibition. Compounds 2g, 2h, 2k, and 2l were found to have IC50 < 10 µM for CDK2. These four compounds were evaluated on EGFR kinase and found to be two times more selective for CDK2. Eight compounds were docked into the CDK2 using Glide software. The docking studies revealed that Lys33 and Leu83 were crucial for binding to CDK2 and docking scores correlate well with the IC50 values. We docked these compounds in EGFR, and they had lower docking scores. Most compounds interacted only with Met769 in EGFR. Molecular dynamic simulation was performed using Desmond software, and the interactions for compounds 2k and 2l with CDK2 were stable.