Research progress of TRK inhibitors and their structure-activity relationship

Neurotrophic tyrosine receptor kinase (NTRK) is a member of the transmembrane receptor tyrosine kinase family. The TRK protein preserves the survival and regular operation of nerve cells and is intimately linked to cell division, proliferation, metabolism, and apoptosis. Any fusion mutations in the NTRK gene with other genes will result in aberrant TRK protein, which causes aberrant cell division and promotes the development of malignancies. As NTRK is the first identified cancer-independent and druggable gene, it is undoubtedly one of the most important anti-cancer targets in the world. However, NTRK gene fusions occur in less than 1 % of solid tumors but are very common in rare tumors, suggesting that early diagnosis is difficult. At the same time, due to the mechanism of targeted or off-target drug resistance, patients become resistant to TRK inhibitors after treatment, and the efficacy is greatly reduced, so it is necessary to conduct further research to overcome the drug resistance problem. In order to provide a theoretical foundation for the development of safer and more effective inhibitors against this target and to expand the range of treatment options available to patients with NTRK gene fusion, this article reviews the mechanism and characteristics of gene fusions, as well as the research status of marketed and investigational targeted therapy drugs.