Trk-IN-20 is a 3-vinylindazole derivative compound that effectively inhibits the functions of Trk kinases. It accomplishes this by suppressing the phosphorylation of TrkA, TrkB, and TrkC, with IC50 values of 1.6 nM, 2.9 nM, and 2.0 nM, respectively [1].

TrkB:2.9 nM, TrkA:1.6 nM, TrkC:2.0 nM

NTRK1 is a proto-oncogene in colon cancer, Trk inhibitors have been detected to against a variety of human cancers [1]. Trk-IN-20 (compound 7mb) (0.031, or 0.018 μM, respectively; 72 h) exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC 50 s of 0.031 and 0.018 μM, respectively [1]. Trk-IN-20 (compound 7mb) (9-22 nM; 72 h) inhibits BaF3 murine cells stably transformed with NTRK oncogenic fusions including CD74-NTRK1, ETV6-NTRK2 and ETV6-NTRK3 with IC 50 s of 15, 22, and 9 nM, respectively [1]. Trk-IN-20 (compound 7mb) (0.32, 1.6, 8, 40, 200; 6 h) inhibits activation of Trk and its downstream proteins in BaF3-CD74-NTRK1, BaF3-ETV6-NTRK2, BaF3-ETV6-NTRK3 cells [1]. Trk-IN-20 (compound 7mb) tightly bound to ATP-binding site of TrkA, TrkB, and TrkC with binding constant (K d ) values of 1.6, 3.1 and 4.9 nM, respectively [1]. Western Blot Analysis [1] Cell Line: BaF3-CD74-NTRK1, BaF3-ETV6-NTRK2, BaF3-ETV6-NTRK3 cells Concentration: 0, 0.32, 1.6, 8, 40, 200 nM Incubation Time: 6 hours Result: Inhibited the phosphorylation of TrkA/B/C and their downstream signaling molecules ERK, AKT, and PLC-γ1. And also induced partial degradation of Trk protein in BaF3-ETV6-NTRK2, BaF3-ETV6-NTRK3 cells.

Trk-IN-20 (compound 7mb) (p.o.; 10 mg/kg) shows short half-life of 1.39 hours and a low oral bioavailability of 8.79% in rats [1]. Animal Model: Pharmacokinetic Profile of Trk-IN-20 (Compound 7mb) in Rats [1] Dosage: Administration: Result: Route Dose (mg/kg) AUC 0-∞ (μM.h) C max (μM) T 1/2 (h) CL (L/h/kg) BA (%) i.v. 2 3.69 6.77 1.39 1.44 / p.o. 10 1.62 0.36 1.13 - 8.79