Trk-IN-20

Trk-IN-20 is a kind of 3-vinylindazole derivatives. Trk-IN-20 suppresses Trk kinases functions by phosphorylation inhibition of TrkA/B/C with IC50 values of 1.6 nM, 2.9 nM and 2.0 nM, respectively[1].

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Trk Receptor

TrkA:1.6 nM (IC50)

TrkB:2.9 nM (IC50)

TrkC:2.0 nM (IC50)

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 IC50s 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 IC50s 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 (Kd) 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) AUC0-∞ (μM.h) Cmax (μM) T1/2 (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

[1]. Duan Y, et al. Design, synthesis, and Structure-Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors. Eur J Med Chem. 2020 Oct 1. 203:112552.