Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Abstract

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (NTRK1, NTRK2 and NTRK3) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLCγ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.

Keywords: AFAP1, actin filament-associated protein 1; AML, acute myeloid leukemia; ARHGEF2, Rho/Rac guanine nucleotide exchange factor 2; BCAN, brevican; BDNF, brain-derived neurotrophic factor; BTBD1, BTB (POZ) domain containing 1; CDK-2, cyclin-dependent kinase 2; CR, complete response; CRC, colorectal cancer; CTCs, sequencing of circulating tumor cells; DFG, Asp-Phe-Gly; DOR, durable objective responses; ETV6, ETS translocation variant 6; EWG, electron-withdrawing group; FDA, U.S. Food and Drug Administration; FISH, fluorescence in situ hybridization; GBM, glioblastoma multiforme; HNSCC, head and neck squamous cell carcinoma; HTS, high-throughput screening; ICC, intrahepatic cholangiocarcinoma; IG-C2, Ig-like C2 type I; LMNA, lamin A/C; MASC, mammary analogue secretory carcinoma; MPRIP, myosin phosphatase Rho interacting protein; NACC2, NACC family member 2; NCCN, National Comprehensive Cancer Network; NFASC, neurofascin; NGF, nerve growth factor; NGS, next-generation sequencing of tumor tissue; NSCLC, non-small cell lung cancer; NT3, neurotrophin-3; NTRK fusion cancer; NTRK, neurotrophic receptor tyrosine kinase; Neurotrophic receptor tyrosine kinase fusions; OAK, osteoarthritis of the knee; ORR, overall response rate; PAN3, poly(A) nuclease 3; PPL, periplakin; PROTAC proteolysis targeting chimera, QKI; RABGTPase activating protein 1-like, RFWD2; RTK, receptor tyrosine kinase; SAR, structure–activity relationship; SBC, secretory breast carcinoma; SCYL3, SCY1 like pseudokinase 3; SQSTM1, sequestosome 1; Small-molecule inhibitor; TFG, TRK-fused gene; TP53, tumor protein P53; TPM3, tropomyosin 3; TPR, translocated promoter region; TRIM24, tripartite motif containing 24; TRK, tropomyosin receptor kinase; Tropomyosin receptor kinase; VCL, vinculin; VEGFR2, vascular endothelial growth factor receptor 2; quaking I protein, RABGAP1L; ring finger and WD repeat domain 2, E3 ubiquitin protein ligase.