3DKF

Structure of MET receptor tyrosine kinase in complex with inhibitor SGX-523


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.

Buchanan, S.G.Hendle, J.Lee, P.S.Smith, C.R.Bounaud, P.Y.Jessen, K.A.Tang, C.M.Huser, N.H.Felce, J.D.Froning, K.J.Peterman, M.C.Aubol, B.E.Gessert, S.F.Sauder, J.M.Schwinn, K.D.Russell, M.Rooney, I.A.Adams, J.Leon, B.C.Do, T.H.Blaney, J.M.Sprengeler, P.A.Thompson, D.A.Smyth, L.Pelletier, L.A.Atwell, S.Holme, K.Wasserman, S.R.Emtage, S.Burley, S.K.Reich, S.H.

(2009) Mol Cancer Ther 8: 3181-3190

  • DOI: https://doi.org/10.1158/1535-7163.MCT-09-0477
  • Primary Citation of Related Structures:  
    3DKC, 3DKF, 3DKG

  • PubMed Abstract: 

    The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.


  • Organizational Affiliation

    SGX Pharmaceuticals, San Diego, CA 92121, USA. buchanan_sean@lilly.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptor317Homo sapiensMutation(s): 3 
Gene Names: METhCG_38705tcag7.66
UniProt & NIH Common Fund Data Resources
Find proteins for P08581 (Homo sapiens)
Explore P08581 
Go to UniProtKB:  P08581
PHAROS:  P08581
GTEx:  ENSG00000105976 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08581
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SX8
Query on SX8

Download Ideal Coordinates CCD File 
C [auth A]6-{[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}quinoline
C18 H13 N7 S
BCZUAADEACICHN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
B [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
SX8 PDBBind:  3DKF Ki: 2.7 (nM) from 1 assay(s)
Binding MOAD:  3DKF Ki: 2.7 (nM) from 1 assay(s)
BindingDB:  3DKF Kd: min: 0.19, max: 3.9 (nM) from 3 assay(s)
IC50: min: 3.1, max: 10 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.089α = 90
b = 46.679β = 90
c = 158.482γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-07-07 
  • Deposition Author(s): Hendle, J.

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-07
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2015-04-22
    Changes: Structure summary
  • Version 1.3: 2021-02-10
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-21
    Changes: Data collection, Database references