Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound exhibited excellent potency against wide type TRKA/C, TRKA, TRKA and TRKA with IC values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC values of 1.43-47.56 nM. Moreover, demonstrated ideal antitumor efficacy in both BaF3-- and BaF3- xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.