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

  • J Med Chem. 2026 Mar 12;69(5):6230-6253. doi: 10.1021/acs.jmedchem.6c00001.
Ying Bai  1 ,  Shiqi Wu  2  1 ,  Wenhui Zhang  1 ,  Yuepeng Chen  1 ,  Wenxin Yan  1 ,  Lei Huang  1 ,  Jing Liu  1 ,  Zhaohui Guan  1 ,  Yupei Su  2 ,  Dongqing Guo  1 ,  Yuchen Bian  1 ,  Kaiyuan Cong  1 ,  Yi Zou  1 ,  Haiping Hao  2 ,  Qihua Zhu  2 ,  Hong Wang  2 ,  Yungen Xu  2  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, RP China.
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, RP China.
PMID: 41739621 DOI: 10.1021/acs.jmedchem.6c00001
Abstract

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, I-16, which exhibits potent and selective inhibition against both PARP1 (IC50 = 0.9 nM) and ERK2 (IC50 = 1.8 nM). Remarkably, I-16 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, I-16 (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 I-16, as the first potent dual PARP1/ERK Inhibitor, represents a promising candidate for Cancer therapy.

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