New pyrrolidine-carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

Cancer is one of the leading causes of mortality worldwide, making it a public
health concern. A novel series of pyrrolidine-carboxamide derivatives 7a-q were
developed and examined in a cell viability assay utilizing a human mammary gland
epithelial cell line (MCF-10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50μM. Antiproliferative
activity was evaluated in vitro against four panels of cancer cell lines A-549, MCF7, Panc-1, and HT-29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active
as antiproliferative agents capable of triggering apoptosis. Compound 7g was the
most potent of all the derivatives, with a mean IC50 of 0.90μM compared to IC50
of 1.10μM for doxorubicin. Compound 7g inhibited A-549 (epithelial cancer cell
line), MCF-7 (breast cancer cell line), and HT-29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o
demonstrated that the tested compounds inhibited EGFR with IC50 values ranging
from 87 to 107nM in comparison with the reference drug erlotinib (IC50=80nM).
7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference
dinaciclib (IC50=20nM), with IC50 values ranging from 15 to 31nM. The results
of inhibitory activity assay against different CDK isoforms revealed that the tested
compounds had preferential inhibitory activity against the CDK2 isoform