PDBsum entry 3v5q

Transferase/transferase inhibitor

PDB id: 3v5q

Contents

Protein chain

263 a.a.

Ligands

0F4 ×2

Metals

_CL

Waters ×189

PDB id:

3v5q

Name:

Transferase/transferase inhibitor

Title:

Discovery of a selective trk inhibitor with efficacy in rodent cancer tumor models

Structure:

Nt-3 growth factor receptor. Chain: a, b. Fragment: kinase domain (unp residues 530-818). Synonym: gp145-trkc, trk-c, neurotrophic tyrosine kinase receptor type 3, trkc tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ntrk3, trkc. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.20Å R-factor: 0.214 R-free: 0.264

Authors:

A.Kreusch

Key ref:

P.Albaugh et al. (2012). Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models. ACS Med Chem Lett, 3, 140-145. PubMed id: 24900443

Date:

16-Dec-11 Release date: 08-Feb-12

Protein chains

Q16288  (NTRK3_HUMAN) -  NT-3 growth factor receptor from Homo sapiens

Seq: 839 a.a.

Struc: 263 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

ACS Med Chem Lett 3:140-145 (2012)

PubMed id: 24900443

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.

P.Albaugh, Y.Fan, Y.Mi, F.Sun, F.Adrian, N.Li, Y.Jia, Y.Sarkisova, A.Kreusch, T.Hood, M.Lu, G.Liu, S.Huang, Z.Liu, J.Loren, T.Tuntland, D.S.Karanewsky, H.M.Seidel, V.Molteni.

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.