TRK-IN-34

TRK-IN-34 is an orally active inhibitor targeting mutant kinases TRKA and TRKC, exhibiting IC50 values of 0.75 nM and 0.96 nM for TRKAG595R and TRKAG667C, respectively. It effectively inhibits the kinase activities of TRKAG595R and TRKAG667C at a functional level. TRK-IN-34 suppresses cell proliferation transfected with TRKA and demonstrates tumor growth inhibition and partial tumor regression in xenograft models. This compound is useful for studying cancers with TRK inhibitor-resistance driven by the TRKAG667C mutation.

TRKA G595R:0.75 nM

TRK-IN-34 (compound 5c) demonstrates excellent metabolic stability in human liver microsomes with a half-life of 153.1 minutes. When applied for three days, TRK-IN-34 effectively inhibits the proliferation of Ba/F3 cells expressing both wild-type and mutant TRKA fusion proteins, with IC50 values of 3 nM, 6 nM, and 17 nM for CD74-NTRK1-WT, CD74-NTRK1-G595R, and CD74-NTRK1-G667C, respectively. At concentrations ranging from 1.23 to 300 nM over 6 hours, it suppresses the phosphorylation of TRKA and downstream signaling proteins PLCγ1 and ERK in a dose-dependent manner in Ba/F3 cells expressing these proteins. Additionally, in cell-free enzyme assays, it potently inhibits wild-type and mutant TRK kinases, with IC50 values against the key resistance mutants TRKA G595R, TRKA G667C, TRKC G623R, and TRKA F589L being 0.75 nM, 0.96 nM, 0.73 nM, and 0.44 nM, respectively.

TRK-IN-34 (compound 5c), administered orally at 30-60 mg/kg twice daily for two consecutive weeks, demonstrates potent, dose-dependent antitumor activity in Ba/F3-LMNA-TRKAG 667C xenograft mouse models. At a dose of 30 mg/kg, the tumor growth inhibition (TGI) is 91%, and at 60 mg/kg, TGI reaches 115%. Additionally, partial tumor regression is observed in 4 out of 6 animals.