What is the mechanism of action of larotrectinib?

LarotrectinibIt is indicated for the treatment of adult and pediatric patients with solid tumors that harbor neurotrophic receptor tyrosine kinase (NTRK) gene fusions without known acquired resistance mutations, are metastatic or where surgical resection may result in significant morbidity, and for which there are no satisfactory alternative therapies or whose disease worsens after treatment.

Larotrectinib is an inhibitor of tropomyosin receptor kinase (TRK), TRKA, TRKB and TRKC. In an extensive set of purified enzyme assays, larotrectinibinhibited TRKA, TRKB and TRKC50 by ICwith values u200bu200bbetween 5-11nm. Another kinase, TNK2, was inhibited at approximately 100 times higher concentrations. TRKA, B and C are encoded by genes pan>NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusion of these genes with different partners produce constitutively activated chimeric TRK fusion proteins that act as oncogenic drivers to promote cell proliferation and survival in tumor cell lines.

In in vitro and in vivo tumor models, larotrectinib showed anti-tumor activity in cells with constitutively activated TRK protein resulting from gene fusion, deletion of the protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinibis least active in cell lines harboring point mutations in the TRKAkinase domain, including the clinically identified acquired resistance mutation G595R . Point mutations in the kinase domain of TRKC that have been clinically determined to confer acquired resistance to larotrectinib include G623R, G696AandF617L. If you want to get more high-quality information, you can contact YaDE. YaDE will do its best to learn more about high-quality overseas drugs for you.