Discovery of the First Highly Selective and Broadly EffectiveMacrocycle-Based Type II TRK Inhibitors that Overcome ClinicallyAcquired Resistance

摘要

Tropomyosin receptor kinase (TRK) secondary mutationsmediating acquired resistance, especially at the solvent-front (SF) and theDFG motif, represent an unmet clinical need. Small-molecule macrocyclic kinaseinhibitors have displayed significant advantages in overcoming clinical resistancedriven by kinase mutations; however, all reported small-molecule macrocyclicTRK inhibitors are all type I inhibitors and are therefore much more sensitive toSF than xDFG mutations. Novel therapeutics for patients with xDFG resistancemutations are urgently needed. We report thefirst highly selective macrocycle-based potent type II TRK inhibitor,7b, that exhibits high inhibitory potencytoward various TRK fusion protein variants as well as wild type.7bexhibitedpotent antiproliferative activity against Ba/F3 cells harboring CD74-TRKAG667Cand ETV6-TRKCG696Cwith half-maximum inhibitory concentration (IC50)values of 6 and 1.7 nM, respectively. More importantly,7balso showed potentantiproliferative activity against a panel of SF mutants (IC50= 5.6-110 nM) and displayed extraordinary kinome selectivity.