Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance

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.