Overview
methylphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea.
- Albaugh, P. et al. (2012) ACS Med. Chem. Lett. 3, 140.
Alomone Labs GNF 5837 inhibits BDNF induced ERK1/2 MAPK phosphorylation in TrkB stably expressed in HEK 293 cells.Cells were serum deprived for 2 hrs followed by a 10 min stimulation with 10 ng/ml Recombinant human BDNF protein (#B-250) (lane 2), 10 and 100 µM GNF 5837 (#G-145) preincubated with 10 ng/ml Recombinant human BDNF protein for 10 min (lanes 3 and 4, respectively). Control cells incubated without Recombinant human BDNF protein are shown in lane 1. Cell proteins were resolved by SDS-PAGE and detected with anti-phospho-ERK1/2.
Three tropomyosin-related kinase (TrkA, TrkB, and TrkC) receptors bind the following neurotrophic factors with varied affinities: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4); BDNF and NT-4 activate TrkB, while NGF and NT-3 activate TrkA and TrkC; NT-3 also activates the other two TRKs, albeit more weakly. After ligand binding, TRKs form dimers, and the subsequent kinase activation results in transphosphorylation of tyrosine residues which in turn enable the binding of cytoplasmic proteins that exhibit phosphotyrosine-binding (PTB) or Src-homology-2 (SH2) domains, such as phospholipase C (PLC-gamma1), p85 and Shc1-3.
GNF-5837 is a novel oxindole urea inhibitor of TRKs. With exceptional binding affinity to TrkA, TrkB, and TrkC (IC50 = 0.011, 0.009, and 0.007 μM/L, respectively), GNF-5837 is a pan-TRK inhibitor that has enhanced selectivity for TRKs, and demonstrates efficiency in mammalian models of tumor. Many carcinomas – not necessarily nerve tissue-related - involve TRK signaling by NTs; GNF-5837 can therefore have useful application in cancer research in addition to other of its many other uses in many biological research branches4,5.
