8W3X

Crystal structure of IRAK4 in complex with compound 6

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 

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Literature

In Retrospect: Root-Cause Analysis of Structure-Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833).

Wright, S.W., Farley, K.A., Han, S., Knafels, J.D., Lee, K.L.

(2024) ACS Med Chem Lett 15: 540-545

  • DOI: https://doi.org/10.1021/acsmedchemlett.4c00036
  • Primary Citation of Related Structures:  
    8W3W, 8W3X

  • PubMed Abstract: 

    In this paper, we disclose insights on the root causes of three structure-activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all- syn (2 S ,3 S ,4 S ) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.

    • Organizational Affiliation: 

    Medicine Design, Pfizer Inc., 445 Eastern Point Rd, Groton, Connecticut 06340, 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
323Homo 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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 142.61α = 90
b = 140.11β = 124.67
c = 87.84γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling
BUSTERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-05-01
    Type: Initial release