6O95

Structure of the IRAK4 kinase domain with compound 41


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.

Bryan, M.C.Drobnick, J.Gobbi, A.Kolesnikov, A.Chen, Y.Rajapaksa, N.Ndubaku, C.Feng, J.Chang, W.Francis, R.Yu, C.Choo, E.F.DeMent, K.Ran, Y.An, L.Emson, C.Huang, Z.Sujatha-Bhaskar, S.Brightbill, H.DiPasquale, A.Maher, J.Wai, J.McKenzie, B.S.Lupardus, P.J.Zarrin, A.A.Kiefer, J.R.

(2019) J Med Chem 62: 6223-6240

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00439
  • Primary Citation of Related Structures:  
    6O8U, 6O94, 6O95, 6O9D

  • PubMed Abstract: 

    A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocrystal structures with the protein and small-molecule crystal structures, yielded a series of dihydrobenzofurans. This semisaturated bicycle provided superior druglike properties while maintaining excellent potency and selectivity. Improved physicochemical properties allowed for progression into in vivo experiments, where lead molecules exhibited low clearance and showed target-based inhibition of IRAK4 signaling in an inflammation-mediated PK/PD mouse model.


  • Organizational Affiliation

    Genentech, Inc. , One DNA Way , South San Francisco , California 94080 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Interleukin-1 receptor-associated kinase 4
A, B, C, D
320Homo 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
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A, B, C, D
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A, B, C, D
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
LSV Binding MOAD:  6O95 Ki: 5.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.838α = 90
b = 140.615β = 123.71
c = 87.559γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-22
    Type: Initial release
  • Version 1.1: 2019-05-29
    Changes: Data collection, Database references
  • Version 1.2: 2019-07-24
    Changes: Data collection, Database references