4RA5

Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.230 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Optimized Protein Kinase C theta (PKC theta ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis.

George, D.M.Breinlinger, E.C.Argiriadi, M.A.Zhang, Y.Wang, J.Bansal-Pakala, P.Duignan, D.B.Honore, P.Lang, Q.Mittelstadt, S.Rundell, L.Schwartz, A.Sun, J.Edmunds, J.J.

(2015) J Med Chem 58: 333-346

  • DOI: https://doi.org/10.1021/jm5013006
  • Primary Citation of Related Structures:  
    4RA4, 4RA5

  • PubMed Abstract: 

    We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.


  • Organizational Affiliation

    AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HUMAN PROTEIN KINASE C THETA
A, B
334Homo sapiensMutation(s): 2 
Gene Names: PRKCQPRKCT
EC: 2.7.11.13
UniProt & NIH Common Fund Data Resources
Find proteins for Q04759 (Homo sapiens)
Explore Q04759 
Go to UniProtKB:  Q04759
PHAROS:  Q04759
GTEx:  ENSG00000065675 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ04759
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A, B
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Binding Affinity Annotations 
IDSourceBinding Affinity
3L0 BindingDB:  4RA5 IC50: 4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.230 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.822α = 90
b = 77.026β = 90
c = 147.547γ = 90
Software Package:
Software NamePurpose
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: 2014-10-08
    Type: Initial release
  • Version 1.1: 2015-02-04
    Changes: Database references