3V5Q

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

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

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.

(2012) ACS Med Chem Lett 3: 140-145

  • DOI: https://doi.org/10.1021/ml200261d
  • Primary Citation of Related Structures:  
    3V5Q

  • 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.


  • Organizational Affiliation

    Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NT-3 growth factor receptor
A, B
297Homo sapiensMutation(s): 0 
Gene Names: NTRK3TRKC
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q16288 (Homo sapiens)
Explore Q16288 
Go to UniProtKB:  Q16288
PHAROS:  Q16288
GTEx:  ENSG00000140538 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16288
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0F4
Query on 0F4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
1-(3-{[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-6-yl]amino}phenyl)-3-[3-(trifluoromethyl)phenyl]urea
C27 H20 F3 N5 O2
JCRUDKWPDBIGME-UCQKPKSFSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
0F4 PDBBind:  3V5Q IC50: 40 (nM) from 1 assay(s)
BindingDB:  3V5Q IC50: 40 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.58α = 90
b = 65.58β = 90
c = 177.252γ = 120
Software Package:
Software NamePurpose
SCALEPACKdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-02-08 
  • Deposition Author(s): Kreusch, A.

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-08
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations