5HNI

CRYSTAL STRUCTURE OF CMET WT with compound 3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.227 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).

Ugolini, A.Kenigsberg, M.Rak, A.Vallee, F.Houtmann, J.Lowinski, M.Capdevila, C.Khider, J.Albert, E.Martinet, N.Nemecek, C.Grapinet, S.Bacque, E.Roesner, M.Delaisi, C.Calvet, L.Bonche, F.Semiond, D.Egile, C.Goulaouic, H.Schio, L.

(2016) J Med Chem 59: 7066-7074

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00280
  • Primary Citation of Related Structures:  
    5HLW, 5HNI, 5HO6, 5HOA, 5HOR

  • PubMed Abstract: 

    The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.


  • Organizational Affiliation

    Sanofi-Aventis Germany GmbH , Industriepark Hoechst, 65926 Frankfurt am Main, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptorA [auth X],
B [auth Y]
312Homo sapiensMutation(s): 0 
Gene Names: MET
EC: 2.7.10.1
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
63B
Query on 63B

Download Ideal Coordinates CCD File 
C [auth X],
D [auth Y]
methyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1H-benzimidazol-2-yl)carbamate
C20 H14 F N7 O2 S
GXKYDDNYCCSFKJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
63B Binding MOAD:  5HNI IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.227 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.853α = 76.96
b = 47.061β = 76.96
c = 81.985γ = 90
Software Package:
Software NamePurpose
CNXrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-23
    Type: Initial release
  • Version 1.1: 2019-10-16
    Changes: Data collection