2. Academic Validation
  3. Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors

Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors

  • J Med Chem. 2025 Jun 12;68(11):11484-11501. doi: 10.1021/acs.jmedchem.5c00412.
Zichao Xu 1,  Yueling Liu 2 3 4,  Peng Wang 1 5,  Xia Peng 2,  Jiawei Cheng 1,  Yinchun Ji 2,  Xutong Li 1,  Dongze Lin 2,  Jing Zhao 1,  Songbin Chen 1,  Zhiyang Xu 1,  Mingyue Zheng 1,  Meiyu Geng 2 3 6 4,  Hong Liu 1 6 7 8,  Jing Ai 2 6 4,  Chunpu Li 1 6 7 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 7 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
  • 8 College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
PMID: 40442078 DOI: 10.1021/acs.jmedchem.5c00412
Abstract

First-generation Trk inhibitors have been effectively employed in clinical oncology treatments. However, acquired resistance frequently develops, primarily attributed to resistant Trk mutants, particularly the prevalent xDFG TrkAG667C mutation. Herein, we unveil the design of novel next-generation Trk inhibitors by leveraging a conformational restriction strategy, beginning with lead compound 7, which was previously discovered by our team. Among them, compound 10o exhibited superior antiproliferative activity in the Ba/F3-MPRIP-TRKAG667C cell line compared to selitrectinib, one of the most advanced selective next-generation Trk inhibitors, and it potently inhibited Trk kinase activity with high selectivity. Furthermore, 10o·HCl showed promising pharmacokinetic profiles with good oral bioavailability in mice. In vivo treatment with 10o·HCl led to a marked delay in tumor growth in a Ba/F3-MPRIP-TRKAG667C subcutaneous tumor model. Thus, our work offers valuable insights for the development of next-generation Trk inhibitors.

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