TRK-IN-31 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 effectively. TRK-IN-31 also significantly suppresses tumor growth in a Ba/F3-MPRIP-TRKAG667C subcutaneous tumor mouse model.

TRK:1.8 nM

TRK-IN-31 (Compound 10o) exhibits significant 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, over 72 hours. At concentrations of 1-20 nM over 2 hours, TRK-IN-31 effectively inhibits TRK signaling in Ba/F3-MPRIP-TRKA and MO-91 cells. It also significantly suppresses TRKA G667C signaling in Ba/F3-MPRIP-TRKA G667C cells at concentrations ranging from 0.04 to 1 μM, with enhanced effects noted at 0.2 μM. Furthermore, TRK-IN-31 at 1 μM over 1 hour demonstrates high selectivity among 92 kinases (S(10): 0.043) and robust inhibition of TRKA/B/C and CSF1R, with inhibition rates between 97% and 103%. TRK-IN-31 shows excellent binding affinity to TRKA G595R, enhancing protein stability and reducing conformational fluctuations.

TRK-IN-31 (Compound 10o) exhibits potent antitumor activity in the Ba/F3-MPRIP-TRKA G667C subcutaneous tumor mouse model when administered orally at doses of 25-150 mg/kg twice daily for 10 consecutive days. It shows a dose-dependent response and maintains good tolerability even at doses up to 150 mg/kg.