2. Academic Validation
  3. Design and synthesis of c-Met/PARP dual-target inhibitors for the treatment of BRCA wild-type TNBC

Design and synthesis of c-Met/PARP dual-target inhibitors for the treatment of BRCA wild-type TNBC

  • Eur J Med Chem. 2026 Apr 15:308:118722. doi: 10.1016/j.ejmech.2026.118722.
Fakai Liu 1,  Qiuhua Huang 1,  Yuan Guo 2,  Shiqi Yang 2,  Fan Sang 2,  Funian Liu 2,  Songlin Lu 2,  Lihong Wu 3,  Zizhou Niu 2,  Xun Zhang 3,  Boren Xiao 2,  Zhichao Shi 4,  Tingting Fan 5,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China; The State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
  • 2 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
  • 3 The State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
  • 4 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. Electronic address: [email protected].
  • 5 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. Electronic address: [email protected].
  • 6 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China; The State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: [email protected].
PMID: 41764804 DOI: 10.1016/j.ejmech.2026.118722
Abstract

Triple-negative breast Cancer (TNBC) is an aggressive subtype characterized by limited treatment options. Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have been approved for the treatment of various types of breast Cancer gene 1/2 (BRCA1/2) mutated cancers, but approximately 80% of TNBC patients do not have BRCA mutations. Leveraging the effects of Other targets on synthetic lethal interactions may be an effective way to broaden the indication of PARP1 inhibitors for TNBC patients with wild-type BRCA. Herein, a series of novel c-Met/PARP dual-target inhibitors based on the moiety of Olaparib were designed and synthesized. Among them, compound L19 potently inhibited c-Met and PARP1 at nanomolar levels and exhibited remarkable antiproliferative activity in BRCA wild-type TNBC cell lines. Meanwhile, compound L19 showed favorable synergistic anti-tumor efficacy in cells by promoting cell cycle arrest and Apoptosis. In particular, L19 exhibited good in vivo antitumor activity (tumor growth inhibition (TGI) rate = 32%) in MDA-MB-231 xenograft models with low toxicity. Taken together, our designed dual c-Met/PARP inhibitors are novel and promising agents for the treatment of BRCA wild-type TNBC.

Keywords

BRCA wild-type TNBC; Dual target inhibitor; PARP; c-Met.

Figures
Products