5KX7

Irak4-inhibitor co-structure


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors.

Hanisak, J.Seganish, W.M.McElroy, W.T.Tang, H.Zhang, R.Tsui, H.C.Fischmann, T.Tulshian, D.Tata, J.Sondey, C.Devito, K.Fossetta, J.Garlisi, C.G.Lundell, D.Niu, X.

(2016) Bioorg Med Chem Lett 26: 4250-4255

  • DOI: https://doi.org/10.1016/j.bmcl.2016.07.048
  • Primary Citation of Related Structures:  
    5KX7, 5KX8

  • PubMed Abstract: 

    IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.


  • Organizational Affiliation

    Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, Unites States. Electronic address: jennifer.hanisak@merck.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Interleukin-1 receptor-associated kinase 4
A, B
301Homo sapiensMutation(s): 0 
Gene Names: IRAK4
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NWZ3 (Homo sapiens)
Explore Q9NWZ3 
Go to UniProtKB:  Q9NWZ3
PHAROS:  Q9NWZ3
GTEx:  ENSG00000198001 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NWZ3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6YD
Query on 6YD

Download Ideal Coordinates CCD File 
C [auth B]~{N}-(3-aminocarbonyl-1-methyl-pyrazol-4-yl)-6-(1-methylpyrazol-4-yl)pyridine-2-carboxamide
C15 H15 N7 O2
XTVOMCVEGADMQN-UHFFFAOYSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A, B
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
6YD BindingDB:  5KX7 IC50: min: 32, max: 138 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.8α = 90
b = 114.28β = 90
c = 139.44γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-17
    Type: Initial release
  • Version 1.1: 2016-08-24
    Changes: Database references