4R1Y

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


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 receptor292Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3EH
Query on 3EH

Download Ideal Coordinates CCD File 
B [auth A]3-(diethylamino)propyl (3-{[5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]methyl}phenyl)carbamate
C26 H34 N4 O5 S
WVYHFPSGWCCXMO-UHFFFAOYSA-N
7PE
Query on 7PE

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL
C14 H30 O7
UKXKPKBTMYNOFS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3EH BindingDB:  4R1Y IC50: min: 400, max: 1100 (nM) from 2 assay(s)
Binding MOAD:  4R1Y IC50: 400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.157α = 90
b = 42.882β = 90
c = 169.502γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
PHASESphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



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