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Defining Molecular Characteristics of First- and Second-Generation TRK Inhibitors

By: Joseph Fanelli
Posted: Monday, November 22, 2021

Research findings presented in Molecular Cancer Therapeutics revealed that second-generation TRK inhibitors may have significantly different potencies against both wild-type and mutant types of TRK in NTRK gene fusions, particularly selitrectinib, the next generation TRK inhibitor with macrocyclic structures. The study of these first- and second-generation TRK inhibitors further revealed the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.

“From this work, subtle but important aspects of compact macrocycle structure are defined that should serve as a foundation for the design of inhibitors that target other oncogenic kinases,” concluded Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center, New York, and colleagues.

In this study, the authors characterized the NTRK inhibitors larotrectinib, entrectinib, selitrectinib, and repotrectinib using cellular models of wild-type TRKA, TRKB, and TRKC fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA.

Of the treatments, repotrectinib was the most potent inhibitor of wild-type TRKA, TRKB, and TRKC fusions and more potent than selitrectinib against all tested resistance mutations. This underscored the importance of distinct features of the macrocycle structures, the authors noted.

Additionally, the authors found the co-crystal structures of repotrectinib with wild-type TRKA and TRKA G595R solvent-front mutations (SMF) variant may explain how macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SMF crystal structure demonstrated an “unexpected” intramolecular arginine sidechain interaction with repotrectinib, leading to tumor regression in LMNA-NTRK1 xenograft models harboring gatekeeper resident, SMF, activation loop, and gatekeeper resident plus SMF compound mutations. The authors also observed durable responses among TKI-naive and TKI-pretreated patients with NTRK-positive cancers treated with repotrectinib.

Disclosure: For full disclosure of the study authors, visit aacrjournals.org.



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