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.