3GFE

Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Pyrazolopyridinone Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.

Wurz, R.P.Pettus, L.H.Xu, S.Henkle, B.Sherman, L.Plant, M.Miner, K.McBride, H.Wong, L.M.Saris, C.J.Lee, M.R.Chmait, S.Mohr, C.Hsieh, F.Tasker, A.S.

(2009) Bioorg Med Chem Lett 19: 4724-4728

  • DOI: https://doi.org/10.1016/j.bmcl.2009.06.058
  • Primary Citation of Related Structures:  
    3GFE

  • PubMed Abstract: 

    A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.


  • Organizational Affiliation

    Department of Chemistry Research & Discovery, Amgen Inc, Thousand Oaks, CA 91320, USA. rwurz@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14366Homo sapiensMutation(s): 0 
Gene Names: MAPK14CSBPCSBP1CSBP2CSPB1MXI2
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens)
Explore Q16539 
Go to UniProtKB:  Q16539
PHAROS:  Q16539
GTEx:  ENSG00000112062 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16539
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P37
Query on P37

Download Ideal Coordinates CCD File 
B [auth A]N-cyclopropyl-3-{[1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-4-methylbenzamide
C24 H21 F2 N5 O2
WMEYCLAVMZKZCS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
P37 PDBBind:  3GFE IC50: 3.2 (nM) from 1 assay(s)
BindingDB:  3GFE IC50: 3.2 (nM) from 1 assay(s)
Binding MOAD:  3GFE IC50: 3.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.419α = 90
b = 87.708β = 90
c = 122.332γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata 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: 2009-07-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations