3V5Q

Discovery of a selective TRK Inhibitor with efficacy in rodent cancer tumor models

Summary for 3V5Q

• Entry DOI: 10.2210/pdb3v5q/pdb
• Descriptor: NT-3 growth factor receptor, CHLORIDE ION, 1-(3-{[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-6-yl]amino}phenyl)-3-[3-(trifluoromethyl)phenyl]urea, ... (4 entities in total)
• Functional Keywords: kinase domain, kinase, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: Q16288
• Total number of polymer chains: 2
• Total formula weight: 68923.39

Authors

Kreusch, A. (deposition date: 2011-12-16, release date: 2012-02-08, Last modification date: 2024-02-28)

Primary citation

Albaugh, P.,Fan, Y.,Mi, Y.,Sun, F.,Adrian, F.,Li, N.,Jia, Y.,Sarkisova, Y.,Kreusch, A.,Hood, T.,Lu, M.,Liu, G.,Huang, S.,Liu, Z.,Loren, J.,Tuntland, T.,Karanewsky, D.S.,Seidel, H.M.,Molteni, V.
Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.
ACS Med Chem Lett, 3:140-145, 2012

PubMed Abstract: Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.

PubMed: 24900443
DOI: 10.1021/ml200261d

Experimental method

X-RAY DIFFRACTION (2.2001 Å)