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

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Cancer remains a leading global cause of mortality, necessitating the development of novel therapeutic agents.
• Pyrrolidine-carboxamide derivatives represent a promising class of compounds for anticancer drug discovery.

Purpose of the Study:

• To synthesize and evaluate a new series of pyrrolidine-carboxamide derivatives for their antiproliferative and cytotoxic effects.
• To identify specific compounds with potent anticancer activity and investigate their mechanism of action, including enzyme inhibition.

Main Methods:

• Synthesis of pyrrolidine-carboxamide derivatives (7a-q).
• In vitro evaluation of cell viability using MCF-10A cells.
• Assessment of antiproliferative activity against A-549, MCF-7, Panc-1, and HT-29 cancer cell lines.
• Inhibition assays for Epidermal Growth Factor Receptor (EGFR) and Cyclin-Dependent Kinase 2 (CDK2).

Main Results:

• All synthesized compounds (7a-q) demonstrated no significant cytotoxicity, maintaining >85% cell viability at 50 μM.
• Compounds 7e, 7g, 7k, 7n, and 7o exhibited significant antiproliferative activity and induced apoptosis.
• Compound 7g showed superior potency (IC50 = 0.90 μM) compared to doxorubicin (IC50 = 1.10 μM) against tested cancer cell lines.
• The most active compounds (7e, 7g, 7k, 7n, 7o) effectively inhibited EGFR (IC50 = 87-107 nM) and CDK2 (IC50 = 15-31 nM), with a preference for CDK2.

Conclusions:

• The novel pyrrolidine-carboxamide derivatives possess significant antiproliferative and apoptosis-inducing properties.
• Compound 7g is a highly potent anticancer agent with potential for further development.
• The observed EGFR and CDK2 inhibitory activities suggest potential mechanisms for the observed anticancer effects.