Recent advances in the discovery of tropomyosin receptor kinases TRKs inhibitors: A mini review

The tropomyosin receptor tyrosine kinases (TRKs) control the cell proliferation mainly in the nervous system and are encoded by NTRK genes. Fusion and mutation of NTRK genes were detected in various types of cancers. Many small molecules TRK inhibitors have been discovered during the last two decades and some of them have entered clinical trials. Moreover, two of these inhibitors; larotrectinib and entrectinib; were approved by FDA for the treatment of TRK-fusion positive solid tumors. However, mutation of TRK enzymes resulted in resistance to both drugs. Therefore, next generation TRK inhibitors were discovered to overcome the acquired drug resistance. Additionally, the off-target and on-target adverse effects on the brain initiated the need for selective TRK subtype inhibitors. Indeed, some molecules were recently reported as selective TRKA or TRKC inhibitors with minimal CNS side effects. The current review highlighted the efforts done during the last three years in the design and discovery of novel TRK inhibitors.

Automated summary

The tropomyosin receptor tyrosine kinases (TRKs), encoded by NTRK genes, regulate cell proliferation in the nervous system and have been found to be fused or mutated in various cancers. Small molecule TRK inhibitors have been developed and some have entered clinical trials, with two (larotrectinib and entrectinib) approved by FDA for treating TRK-fusion positive solid tumors. However, resistance to these drugs due to TRK enzyme mutations has been observed. Therefore, next generation TRK inhibitors have been discovered to overcome acquired resistance, and selective TRK subtype inhibitors with minimal CNS side effects have also been reported. This review summarizes the efforts made in the past three years in the design and discovery of novel TRK inhibitors.