Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation

Tropomyosin
receptor kinase (TRK) inhibition is an effective therapeutic
approach for treatment of a variety of cancers. Despite the use of
first-generation TRK inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired
resistance develops invariably. The emergence of secondary mutations
occurring at the solvent-front, xDFG, and gatekeeper regions of TRK
represents a common mechanism for acquired resistance. However, xDFG
mutations remain insensitive to second-generation macrocyclic TRKIs
selitrectinib (3) and repotrectinib (4)
designed to overcome the resistance mediated by solvent-front and
gatekeeper mutations. Here, we report the structure-based drug design
and discovery of a next-generation TRKI. The structure–activity
relationship studies culminated in the identification of a promising
drug candidate 8 that showed excellent in vitro potency on a panel of TRK mutants, especially TRKAG667C in the xDFG motif, and improved in vivo efficacy
than 1 and 3 in TRK wild-type and mutant
fusion-driven tumor xenograft models, respectively.