Molecular Boomerangs Against Cancer: Design, Synthesis, Biological Evaluation, and In Silico Study of Novel Dual...

A possible method for improving anti-cancer efficacy is the combination of the inhibition of epidermal growth factor receptor (EGFR) and poly (ADP-ribose) polymerase-1 (PARP-1). This work describes the rational design, synthesis, and complete characterization of a novel class of boomerang-shaped dual PARP-1/EGFR inhibitors (3a-o). HepG-2 and MDA-MB-231 cancer cell lines were used to test the synthesized compounds' antiproliferative potential; MDA-MB-231 cells showed greater sensitivity. Compounds 3h, 3i, and 3j had the strongest cytotoxic effects among the series, with IC₅₀ values of 0.23, 0.90, and 1.40 µM, respectively, against MDA-MB-231 cells. Compared with the reference medications erlotinib and olaparib, compound 3h showed the highest dual inhibition (EGFR IC₅₀ = 1.62 µM and PARP-1 IC₅₀ = 0.36 µM) in enzymatic experiments, demonstrating that these compounds effectively inhibited both EGFR and PARP-1. Compound 3h strongly promoted apoptosis in MDA-MB-231 cells, increasing the total apoptotic population to 20.04% and causing G1-phase cell-cycle arrest, as determined by mechanistic studies. In vivo tumor growth inhibition trials showed a tumor inhibition rate (TIR%) of 41.4% for compound 3h compared to 48.8% for doxorubicin (DOX). Liver function biomarkers and hematological parameters remained within the acceptable levels following compound 3h treatment. The dual-target activity of compound 3h was further validated by molecular docking and molecular dynamics simulations, which demonstrated persistent binding contacts within the active sites of PARP-1 and EGFR.