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 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.