Discovery of Novel and Potent Dual PARP1/ERK Inhibitors as a Promising Strategy for Cancer Therapy

The clinical application of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors is frequently constrained by drug resistance and clinical efficacy. Suppression of the extracellular signal-regulated kinase (ERK) pathway can impair homologous recombination (HR) repair and sensitize cancer cells to PARP1 inhibition. Capitalizing on this synthetic lethal interaction, we designed and developed a novel dual PARP1/ERK inhibitor, <b>I-16</b>, which exhibits potent and selective inhibition against both PARP1 (IC₅₀ = 0.9 nM) and ERK2 (IC₅₀ = 1.8 nM). Remarkably, <b>I-16</b> displayed strong antiproliferative activity across a panel of cancer cell lines, including both breast cancer susceptibility genes (BRCA) mutant and BRCA-wild-type models. In an HCT116 xenograft model, <b>I-16</b> (20 mg/kg) elicited significant tumor growth suppression, outperforming Olaparib (50 mg/kg) or BVD-523 (5 mg/kg) monotherapy and achieving efficacy comparable to their combination. These findings suggest that <b>I-16</b>, as the first potent dual PARP1/ERK inhibitor, represents a promising candidate for cancer therapy.