Cyanopyridine-based derivatives as potent anticancer agents: Integrating in silico analysis and in vitro biological targeting of the EGFR/AKT/MAPK Signaling Cascade.

Abstract

The increasing global incidence of cancer and the recurrent development of resistance to standard treatments require a rapid development of innovative, multi-targeted chemotherapeutic medicines. This study focused on the strategic design and synthesis of a range of new cyanopyridine derivatives (1a,b-5a,b) targeting the critical oncogenic kinases. The antiproliferative efficacy of these derivatives was assessed against the breast cancer cell line (MCF-7) and the colorectal cancer cell line (HCT116), demonstrating moderate to significant inhibitory activity, with IC50 values ranging from 6.93 to 43.49 μM. Compound 2b emerged as the most selective and potent derivative in the series, showing greater activity against HCT116 cells (IC50 = 7.34 μM) compared to MCF-7 cells (IC50 = 17.55 μM). Experimental investigations demonstrated that compound 2b exerts its anticancer effects by inducing apoptosis and initiating G0-G1 cell cycle arrest. Moreover, compound 2b was identified as an effective inhibitor of key tumor-promoting signaling pathways, including EGFR (IC50 = 0.300 μM), AKT (IC50 = 0.706 μM), ERK (IC50 = 0.143 μM), and p38-MAPKα (IC50 = 0.308 μM). The structural design was validated by molecular docking simulations and molecular dynamics simulations, which revealed favorable binding affinities to the target kinases' active sites. In silico ADME analysis of compound 2b showed favorable drug-like properties, including compliance with the Veber rules and a bioavailability score of 0.55. The combined results underscore the promise of the cyanopyridine scaffold as a framework for developing selective multi-target anticancer medicines.