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, TRKAG595R, TRKAG667C, and TRKAF589L 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-NTRK1G595R and BaF3-CD74-NTRK1G667C xenograft models. The study provides a promising
lead compound for pan-anticancer drug discovery.