Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the
Zichao Xu1, Yueling Liu2,3,4, Peng Wang1,5
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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.
Insights
Novel next-generation TRK inhibitors were designed using a conformational restriction strategy to overcome acquired resistance mutations, such as TRKAG667C. Compound 10o demonstrated superior efficacy and favorable pharmacokinetics, offering new therapeutic insights.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- First-generation TRK inhibitors are clinically used but face acquired resistance, often due to TRK mutations like TRKAG667C.
- Developing next-generation inhibitors is crucial to overcome resistance and improve cancer treatment outcomes.
Purpose of the Study:
- To design and synthesize novel next-generation TRK inhibitors employing a conformational restriction strategy.
- To evaluate the efficacy of these inhibitors against resistant TRK mutants, specifically TRKAG667C.
Main Methods:
- Lead compound 7 was utilized as a starting point for designing new inhibitors.
- Compound 10o was synthesized and tested for antiproliferative activity in Ba/F3-MPRIP-TRKAG667C cells.
- Pharmacokinetic profiles and *in vivo* efficacy in a TRKAG667C tumor model were assessed.
Main Results:
- Compound 10o showed superior antiproliferative activity against TRKAG667C compared to selitrectinib.
- 10o potently and selectively inhibited TRK kinase activity.
- 10o·HCl exhibited favorable pharmacokinetics, including good oral bioavailability in mice, and delayed tumor growth *in vivo*.
Conclusions:
- The conformational restriction strategy successfully yielded potent next-generation TRK inhibitors effective against resistant mutants.
- Compound 10o represents a promising candidate for further development in TRK-driven cancers.
- This research provides valuable insights for designing future TRK inhibitors to combat acquired resistance.
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