Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance
Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Zhimin Zhang, Zhang Zhang, Ke Ding, Xiaoyun Lu
Abstract
Tropomyosin receptor kinase (TRK) secondary mutations mediating acquired resistance, especially at the solvent-front (SF) and the DFG motif, represent an unmet clinical need. Small-molecule macrocyclic kinase inhibitors have displayed significant advantages in overcoming clinical resistance driven by kinase mutations; however, all reported small-molecule macrocyclic TRK inhibitors are all type I inhibitors and are therefore much more sensitive to SF than xDFG mutations. Novel therapeutics for patients with xDFG resistance mutations are urgently needed. We report the first highly selective macrocycle-based potent type II TRK inhibitor, 7b, that exhibits high inhibitory potency toward various TRK fusion protein variants as well as wild type. 7b exhibited potent antiproliferative activity against Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C with half-maximum inhibitory concentration (IC50) values of 6 and 1.7 nM, respectively. More importantly, 7b also showed potent antiproliferative activity against a panel of SF mutants (IC50 = 5.6–110 nM) and displayed extraordinary kinome selectivity.