4R1V

Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.146 
  • R-Value Observed: 0.146 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.

Dorsch, D.Schadt, O.Stieber, F.Meyring, M.Gradler, U.Bladt, F.Friese-Hamim, M.Knuhl, C.Pehl, U.Blaukat, A.

(2015) Bioorg Med Chem Lett 25: 1597-1602

  • DOI: https://doi.org/10.1016/j.bmcl.2015.02.002
  • Primary Citation of Related Structures:  
    4R1V, 4R1Y

  • PubMed Abstract: 

    In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development.


  • Organizational Affiliation

    Merck Serono Research & Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany. Electronic address: dieter.dorsch@merckgroup.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptor291Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
3E8 BindingDB:  4R1V IC50: min: 1, max: 100 (nM) from 4 assay(s)
Binding MOAD:  4R1V IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.146 
  • R-Value Observed: 0.146 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38α = 90
b = 43.038β = 92.23
c = 84.844γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
PHASESphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-18
    Type: Initial release
  • Version 1.1: 2015-04-22
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations