GNF-5837 is a potent pan-Trk inhibitor which display antiproliferative effects in cellular Ba/F3 assays (IC50 values are 7, 9 and 11 nM for cells containing the fusion proteins Tel-TrkC, Tel-TrkB and Tel-TrkA, respectively).
The tropomyosin receptor kinase (TRK) family includes three members of highly homologous receptor tyrosine kinases, TRKA, TRKB, and TRKC that specifically bind to neurotrophins. The binding of neutrophins to the extracellular domains of TRKs causes the kinases to autophosphorylate at several intracellular tyrosine sites and trigger downstream signals involving RAS/ERK, PI3K/AKT, and PLC-γ1 transduction pathways.
GNF-5837 is a selective inhibitor of TRKs with IC50s of 8nM and 12nM for TRKA and TRKB, respectively[3]. In proliferation assays utilizing TRK dependent Ba/F3 cells, the inhibitory IC50s of GNF-5837 against cells containing the fusion proteins Tel-TRKA, Tel-TRKB and Tel-TRKC were 11nM, 9nM and 7nM, respectivelyv. In GOT1 cell lines, 2h treatment of GNF-5837 at the concentration of 10nM blocked TRKA activation upon NGF stimulation. The IC50 of GNF-5837 on GOT1 cell proliferation after 144h of incubation was ～660nM. At the concentrations of 5nM, 50nM and 500nM, 24h treatment of GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling and Ras-Raf-MEK-ERK signaling[4]. In xenografts of RIE cells expressing both TRKA and NGF, GNF-5837 was orally administrated daily for 10 days. 72% and 100% tumor regression was observed at the doses of 50mg/kg and 100mg/kg, respectively, while at 25 mg/kg, only partial tumor growth inhibition was achieved[3].
GNF-5837 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
BA/F3 cells
Proliferation assay
Antiproliferative activity against mouse BA/F3 cells expressing Tel-TRKC, IC50=7 nM
24900443
Mo7e cells
Function assay
Inhibition of c-Kit in human Mo7e cells, IC50=1 μM
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