3ZCL

X-ray Structure of c-Met kinase in complex with inhibitor (S)-3-(1-(1H-pyrrolo(2,3-b)pyridin-3-yl)ethyl)-N-isopropyl-(1,2,4)triazolo(4,3- b)pyridazin-6-amine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Lessons from (S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2, 4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), an Inhibitor of Receptor Tyrosine Kinase C-met with High Protein Kinase Selectivity But Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats.

Cui, J.J.Shen, H.Tran-Dube, M.Nambu, M.Mctigue, M.Grodsky, N.Ryan, K.Yamazaki, S.Aguirre, S.Parker, M.Li, Q.Zou, H.Christensen, J.

(2013) J Med Chem 56: 6651

  • DOI: https://doi.org/10.1021/jm400926x
  • Primary Citation of Related Structures:  
    3ZBX, 3ZC5, 3ZCL

  • PubMed Abstract: 

    The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.


  • Organizational Affiliation

    La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEPATOCYTE GROWTH FACTOR RECEPTOR306Homo sapiensMutation(s): 0 
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
5TF
Query on 5TF

Download Ideal Coordinates CCD File 
B [auth A](S)-3-(1-(1H-pyrrolo(2,3-b)pyridin-3-yl)ethyl)-N-isopropyl-(1,2,4)triazolo(4,3-b)pyridazin-6-amine
C17 H19 N7
PUIUZHJXBDSQEZ-NSHDSACASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5TF BindingDB:  3ZCL Ki: 10 (nM) from 1 assay(s)
IC50: 19 (nM) from 1 assay(s)
PDBBind:  3ZCL Ki: 10.1 (nM) from 1 assay(s)
Binding MOAD:  3ZCL Ki: 10.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.997α = 90
b = 94.509β = 90
c = 46.834γ = 90
Software Package:
Software NamePurpose
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-27
    Type: Initial release
  • Version 1.1: 2019-05-08
    Changes: Data collection, Experimental preparation, Other
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description