AI Article Synopsis
- TRK inhibition is a promising way to treat various cancers, but resistance often develops due to mutations in specific regions of the TRK protein.
- First-generation TRK inhibitor larotrectinib shows good results, but certain mutations make it less effective, particularly xDFG mutations which resist newer drugs selitrectinib and repotrectinib.
- Researchers have designed a next-generation TRK inhibitor that targets these resistant mutants more effectively, showing better performance in lab models compared to existing treatments.
Article Abstract
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 () 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 () and repotrectinib () 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 that showed excellent potency on a panel of TRK mutants, especially TRKA in the xDFG motif, and improved efficacy than and in TRK wild-type and mutant fusion-driven tumor xenograft models, respectively.
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