Discovery of a Novel and Potent MET Transcription Inhibitor Targeting Promoter G-Quadruplex for the Treatment of NSCLC

  • J Med Chem. 2025 Jun 12;68(11):10845-10859. doi: 10.1021/acs.jmedchem.4c03039.
Wenjian Min  1  2 ,  Chunling Chen  1  2 ,  Zhongrui Shi  1  2 ,  Huanaoyu Yang  1  2 ,  Yanyin Wang  1  2 ,  Junfeng He  1  2 ,  Qiman Zhang  1  2 ,  Yunchu Zhao  1 ,  Yi Hou  1  2 ,  Jiayu Ding  1  2 ,  Yasheng Zhu  1  2 ,  Chengliang Sun  1  2 ,  Kai Yuan  1  2 ,  Peng Yang  1  2  3 ,  Xiao Wang  1  2  3
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
PMID: 40457545 DOI: 10.1021/acs.jmedchem.4c03039
Abstract

c-Met is a promising molecular target in oncological treatment, and related targeted therapy drugs have achieved inspiring results in clinical practice. However, the clinical emergence of acquired resistance to c-Met inhibitors in recent years presents a significant therapeutic challenge. In this study, we identified a novel MET transcriptional inhibitor, C3, which efficiently binds to the G-quadruplex in the MET promoter and suppresses the expression of c-Met. Meanwhile, C3 exhibited potent antitumor activity against nonsmall cell lung Cancer (NSCLC) cells and xenograft tumor models. Importantly, as a MET transcription inhibitor, C3 demonstrated superior efficacy compared to conventional c-Met inhibitors in suppressing proliferation in Ba/F3 cell lines, harboring defined c-Met mutations. Thus, C3 could serve as a promising lead for the treatment of NSCLC.

Products