2. Academic Validation
  3. Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met amplification-mediated PARP1i acquired-resistance

Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met amplification-mediated PARP1i acquired-resistance

  • Eur J Med Chem. 2025 Dec 15:300:118164. doi: 10.1016/j.ejmech.2025.118164.
Zeren Sun 1,  Mengxuan Hu 2,  Jie Xu 1,  Bingxin Zhai 1,  Yuchen Zhang 1,  Wenbin Zhang 1,  Boning Wang 1,  Runyuan Wang 1,  Zheqi Hu 1,  Yungen Xu 3,  Qihua Zhu 4,  Yi Zou 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; The Third Department of Pharmacy, The First Affiliated Hospital of He'nan Polytechnic University, Henan, 454000, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: xyg@cpu.edu.cn.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zhuqihua@vip.126.com.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zouyi@cpu.edu.cn.
PMID: 40957266 DOI: 10.1016/j.ejmech.2025.118164
Abstract

PARP1 is a well-established therapeutic target in Cancer treatment, based on the principle of synthetic lethality. However, the development of drug resistance has significantly compromised the antitumor efficacy of PARP1 inhibitors, exemplified by resistance mediated through c-Met amplification. In this study, we report the development of a novel PARP1/c-Met dual inhibitor derived from the benzofuran-7-carboxamide moiety of the PARP1 Inhibitor Mefuparib. Compared with compound 16 obtained in the previous study, compound S12 was identified as a highly potent dual inhibitor with lower molecule weight and better solubility, demonstrating robust inhibitory activity against both PARP1 (IC50 = 21.8 nM) and c-Met (IC50 = 30.2 nM). Importantly, S12 exhibited remarkable anti-tumor efficacy in the HCT116OR xenograft models, suggesting that targeting both PARP1 and c-Met represents an effective therapeutic strategy to overcome PARP1 Inhibitor resistance mediated by c-Met amplification.

Keywords

Acquired drug-resistance; Dual target inhibitor; PARP1; c-Met.

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