JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo.

ABSTRACT: The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupie

SUBMITTER: Wang J 

PROVIDER: S-EPMC9570838 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature