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

作者：Zichao Xu, Yueling Liu, Peng Wang, Peng Xia, Jiawei Cheng, Yinchun Ji, Xutong Li, Dongze Lin, Jian Zhao, Songbin Chen, Zhiyang Xu, Mingyue Zheng, Meiyu Geng, Hong Liu, Jing Ai, Chunpu Li · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00412 · 被引用次数：3 · 研究领域：Cancer Mechanisms and Therapy、Cancer therapeutics and mechanisms、Protein Degradation and Inhibitors

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 TRKA G667C 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-TRKA G667C 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-TRKA G667C subcutaneous tumor model. Thus, our work offers valuable insights for the development of next-generation TRK inhibitors.