2. Academic Validation
  3. Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression

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

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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