2. Academic Validation
  3. Discovery of Novel and Potent Dual PARP1/ERK Inhibitors as a Promising Strategy for Cancer Therapy

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

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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