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

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

“…Similar to other receptor tyrosine kinase inhibitors, off-target alterations also mediated acquired resistances to TRK inhibitors 30 , 87 , 88 . Previous studies have demonstrated acquired BRAF V600E , KRAS G12D mutations as well as MET amplification render resistance to the 1st-generation inhibitors larotrectinib and entrectinib in clinic 30 .…”

Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with small molecules

“…To improve activity against Trk solvent front and DFG mutations, constrained macrocyclic derivatives of larotrectinib were synthesized (Scheme 6), which uncovered 19 (selitrectinib, LOXO-195) and 20 (repotrectinib, TPX-0005). 20,82,83 These macrocycles were designed with conformational rigidity to avoid steric clashes with TrkA G595R , TrkA G667C , and TrkC G623R secondary kinase mutations. Molecular modeling indicated that selitrectinib and repotrectinib both bind to the Trk active site without steric clashes with solvent front or gatekeeper mutations (Fig.…”

Mutation of neurotrophic tyrosine receptor kinase can promote pan-cancer immunity and the efficacy of immunotherapy

“…Mutations of NTRK genes are frequently detected in various tumors. They can trigger a number of signal pathways that regulate cell growth, proliferation, differentiation, apoptosis and survival [ 3 ], which may impact the tumor immunogenicity. Indeed, previous studies revealed that colorectal tumors harboring NTRK fusions defined a unique subtype with high microsatellite instability [ 4 ].…”