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 10g exhibited excellent potency against wide type TRKA/C, TRKA(G595R), TRKA(,)(G667C) and TRKA(F589L) with IC50 values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC50 values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1(G595R) and BaF3-CD74-NTRK1(G667C) xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

Automated summary

This study focuses on the development of new type II TRK inhibitors to combat acquired resistance mutations. Compound 10g displayed excellent potency against TRK mutants and demonstrated strong inhibition of cell proliferation. The results provide a promising lead compound for pan-anticancer drug discovery.