Molecular Boomerangs Against Cancer: Design, Synthesis, Biological Evaluation, and In Silico Study of Novel Dual PARP‐1/EGFR Inhibitors

ABSTRACT 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 IC 50 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 IC 50 = 1.62 µM and PARP‐1 IC 50 = 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.