TRK-IN-31 hydrochloride is an orally active TRK inhibitor with an IC50 of 1.8 nM. It demonstrates excellent antiproliferative activity in Ba/F3-MPRIP-TRKAG667C cells and selectively inhibits TRK kinase activity. Additionally, TRK-IN-31 hydrochloride significantly suppresses tumor growth in a Ba/F3-MPRIP-TRKAG667C subcutaneous mouse model.

TRK:1.8 nM

TRK-IN-31 hydrochloride (Compound 10o•HCl) demonstrates potent antiproliferative activity with IC50 values of 81.4 nM and 131.4 nM against Ba/F3-MPRIP-TRKA G667C and Ba/F3-MPRIP-TRKA G595R cells, respectively. At concentrations of 1-20 nM for 2 hours, it significantly inhibits TRK signaling in Ba/F3-MPRIP-TRKA and MO-91 cells. Furthermore, TRK-IN-31 hydrochloride at 0.04-1 μM over 2 hours effectively suppresses TRKA G667C signaling in Ba/F3-MPRIP-TRKA G667C cells, with peak efficacy at 0.2 μM. At 1 μM for 1 hour, it exhibits high selectivity among 92 kinases (S(10): 0.043), markedly inhibiting TRKA/B/C and CSF1R with inhibition rates of 97%-103%. In addition, TRK-IN-31 hydrochloride has exceptional binding affinity for TRKA G595R, improving protein stability and reducing conformational fluctuations.

TRK-IN-31 hydrochloride (Compound 10o•HCl) demonstrates potent antitumor effectiveness in a dose-dependent manner when administered orally at 25-150 mg/kg twice daily over 10 days in a Ba/F3-MPRIP-TRKA G667C subcutaneous tumor mouse model, showing good tolerability even at the highest dose of 150 mg/kg.