Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors
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<sup>G667C</sup> mutation. Herein, we unveil the design of novel next-generation TRK inhibitors by leveraging a conformational restriction strategy, beginning with lead compound <b>7</b>, which was previously discovered by our team. Among them, compound <b>10o</b> exhibited superior antiproliferative activity in the Ba/F3-MPRIP-TRKA<sup>G667C</sup> cell line compared to <b>selitrectinib,</b> one of the most advanced selective next-generation TRK inhibitors, and it potently inhibited TRK kinase activity with high selectivity. Furthermore, <b>10o·HCl</b> showed promising pharmacokinetic profiles with good oral bioavailability in mice. <i>In vivo</i> treatment with <b>10o·HCl</b> led to a marked delay in tumor growth in a Ba/F3-MPRIP-TRKA<sup>G667C</sup> subcutaneous tumor model. Thus, our work offers valuable insights for the development of next-generation TRK inhibitors.
Authors
- Zichao Xu
- Dongze Lin
- Xutong Li (ORCID: https://orcid.org/0000-0001-9547-0643)
- Meiyu Geng (ORCID: https://orcid.org/0000-0002-7362-0847)
- Yueling Liu (ORCID: https://orcid.org/0000-0001-7595-3293)
- Chunpu Li (ORCID: https://orcid.org/0000-0002-3000-0728)
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Shanyuan Chen (ORCID: https://orcid.org/0000-0002-9524-9428)
- Hong Shu Liu (ORCID: https://orcid.org/0000-0003-3685-6268)
- Jiawei Cheng (ORCID: https://orcid.org/0009-0000-2338-0972)
- Jian Zhao (ORCID: https://orcid.org/0000-0002-8862-0591)
- Zhiyang Xu (ORCID: https://orcid.org/0000-0002-8294-4229)
- Jing Ai (ORCID: https://orcid.org/0000-0003-3717-981X)
- Peng Xia (ORCID: https://orcid.org/0000-0002-6046-3790)
- Yinchun Ji
- Peng Wang
Institutions
- Xinjiang Medical University (CN)
- China Pharmaceutical University (CN)
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
- Advanced Research Institute (US)
- Institute for Advanced Study (DE)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00412
- Citations
- 3
- Primary Topic
- Cancer Mechanisms and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 4.41
Funders
- National Natural Science Foundation of China
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- National Key Research and Development Program of China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences