5VIO

Crystal structure of ASK1 kinase domain with a potent inhibitor (analog 13)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.84 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors.

Lovering, F.Morgan, P.Allais, C.Aulabaugh, A.Brodfuehrer, J.Chang, J.Coe, J.Ding, W.Dowty, H.Fleming, M.Frisbie, R.Guzova, J.Hepworth, D.Jasti, J.Kortum, S.Kurumbail, R.Mohan, S.Papaioannou, N.Strohbach, J.W.Vincent, F.Lee, K.Zapf, C.W.

(2017) Eur J Med Chem 145: 606-621

  • DOI: https://doi.org/10.1016/j.ejmech.2017.12.041
  • Primary Citation of Related Structures:  
    5VIL, 5VIO

  • PubMed Abstract: 

    Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition.


  • Organizational Affiliation

    Medicine Design, Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA. Electronic address: frank.lovering@pfizer.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase kinase kinase 5
A, B, C, D
293Homo sapiensMutation(s): 0 
Gene Names: MAP3K5ASK1MAPKKK5MEKK5
EC: 2.7.11.25
UniProt & NIH Common Fund Data Resources
Find proteins for Q99683 (Homo sapiens)
Explore Q99683 
Go to UniProtKB:  Q99683
PHAROS:  Q99683
GTEx:  ENSG00000197442 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99683
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9E4
Query on 9E4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B],
G [auth D]
4-methoxy-N~1~-methyl-N~3~-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}benzene-1,3-dicarboxamide
C20 H22 N6 O3
WOQOZRHVLYUXPM-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
9E4 BindingDB:  5VIO IC50: min: 2.4, max: 272 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.84 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.39α = 90
b = 132.43β = 92.29
c = 135.63γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
autoPROCdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 1.1: 2018-01-31
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Refinement description