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].

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

Trk-IN-20 (compound 7mb), identified as a potent inhibitor of Trk kinases, demonstrates significant efficacy against Larotrectinib-resistant colon cancer cells harboring NTRK1-G667C or NTRK3-G696A mutations, with IC50 values of 0.031 and 0.018 µM, respectively. Additionally, it effectively suppresses the activation of Trk and its downstream proteins in BaF3 murine cells expressing oncogenic NTRK fusions (CD74-NTRK1, ETV6-NTRK2, and ETV6-NTRK3), showcasing IC50s ranging from 9 to 22 nM. Further evaluations reveal that Trk-IN-20 binds tightly to the ATP-binding sites of TrkA/B/C with low nanomolar affinity (Kd values between 1.6 and 4.9 nM) and inhibits downstream signaling molecules such as ERK, AKT, and PLC-γ1 in a concentration-dependent manner, while also inducing partial degradation of Trk proteins in certain cell lines. These findings, supported by Western Blot analysis, underscore Trk-IN-20's potential as a targeted therapy for diverse human cancers with NTRK gene fusions.

Trk-IN-20 (compound 7mb), administered orally at a dosage of 10 mg/kg, exhibits a short half-life of 1.39 hours and low oral bioavailability of 8.79% in rats. This indicates a rapid clearance from the body and limited absorption when administrated by mouth. The pharmacokinetic data, including area under the curve (AUC), maximum concentration (Cmax), half-life (T1/2), and clearance rate (CL) for both intravenous (i.v.) and oral (p.o.) routes, suggest a significant difference in the drug's absorption and distribution in the animal model [1].