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説明

Tropomyosin-related kinases (Trks) are receptor tyrosine kinases activated by peptides, including neurotrophins. They have prominent roles in the development of central and peripheral nervous systems, vascular cell survival, and cancer. Rearrangement of genes for Trks with the transcription factor Tel, producing Tel-Trk fusion proteins, are associated with various types of cancer. GNF-5837 is a potent, bioavailable pan-Trk inhibitor that blocks the proliferation of cells expressing Tel-TrkA, Tel-TrkB, and Tel-TrkC (IC50s = 7, 9, and 11 nM, respectively). It less effectively inhibits c-Kit and PDGFRβ (IC50s = 0.91 and 0.87 μM, respectively), while requiring micromolar concentrations to inhibit an array of other receptor and non-receptor tyrosine kinases. GNF-5837 inhibits the growth of Ba/F3 and rat intestinal epithelial (RIE) cells expressing both TrkA and nerve growth factor (NGF) with IC50 values of 42 and 17 nM, respectively, but does not have anti-proliferative activity of parental cells at concentrations up to 10 μM. GNF-5837 displays good bioavailability in mice and rats when given intravenously but not orally. It induces regression of tumor xenografts derived from RIE cells expressing both TrkA and NGF.