Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression

  • J Med Chem. 2024 Mar 28;67(6):4916-4935. doi: 10.1021/acs.jmedchem.4c00077.
Zeren Sun  1 ,  Lanjie Li  1 ,  Bingxin Zhai  1 ,  Mengxuan Hu  1 ,  Lei Huang  1 ,  Shihui Huang  1 ,  Liu Ye  1 ,  Xiangying Kong  1 ,  Jie Xu  1 ,  Jie Bai  2 ,  Jingjie Yan  2 ,  Qichen Zhou  1 ,  Zheqi Hu  1 ,  Yuchen Zhang  1 ,  Yuhan Jiang  2 ,  Yan Zhang  2 ,  Zhou Qiao  3 ,  Yi Zou  1  2 ,  Yungen Xu  1  2 ,  Qihua Zhu  1  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. China Pharmaceutical University Center for Analysis and Testing, China Pharmaceutical University, Nanjing 211198, China.
PMID: 38477575 DOI: 10.1021/acs.jmedchem.4c00077
Abstract

The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC50 = 3.3 nM) and c-Met (IC50 = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient Cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 Inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.

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