Definition

An orally bioavailable, second-generation tropomyosin-related-kinase (TRK) inhibitor, with potential antineoplastic activity. Upon oral administration, TRK inhibitor VC004 specifically targets and binds to TRK, TRK mutations and fusion proteins containing sequences from neurotrophic tyrosine receptor kinase (NTRK) types 1 (NTRK1; TrkA), 2 (NTRK2; TrkB), and 3 (NTRK3; TrkC). This inhibits neurotrophin-TRK interaction and TRK activation, thereby preventing the activation of downstream signaling pathways, including the PI3K, RAS/MAPK/ERK and PLC-gamma pathways that are activated by these kinases. This results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress TRK and/or express NTRK fusion proteins. TRK, a family of receptor tyrosine kinases (RTKs) activated by neurotrophins, is encoded by NTRK family genes. The expression of either mutated forms of, or fusion proteins involving NTRK family members results in uncontrolled TRK signaling, which plays an important role in tumor cell growth, survival, invasion and treatment resistance.