6EYZ

PI3 kinase delta in complex with 4-Fluorophenyl 5-(4-(5-((4-isopropylpiperazin-1-yl)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxynicotinate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Selectively Targeting the Kinome-Conserved Lysine of PI3K delta as a General Approach to Covalent Kinase Inhibition.

Dalton, S.E.Dittus, L.Thomas, D.A.Convery, M.A.Nunes, J.Bush, J.T.Evans, J.P.Werner, T.Bantscheff, M.Murphy, J.A.Campos, S.

(2018) J Am Chem Soc 140: 932-939

  • DOI: https://doi.org/10.1021/jacs.7b08979
  • Primary Citation of Related Structures:  
    6EYZ, 6EZ6

  • PubMed Abstract: 

    Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ∼200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.


  • Organizational Affiliation

    Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform1,051Mus musculusMutation(s): 0 
Gene Names: Pik3cd
UniProt
Find proteins for O35904 (Mus musculus)
Explore O35904 
Go to UniProtKB:  O35904
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO35904
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C5W (Subject of Investigation/LOI)
Query on C5W

Download Ideal Coordinates CCD File 
B [auth A]2-methoxy-5-[4-[5-[(4-propan-2-ylpiperazin-1-yl)methyl]-1,3-oxazol-2-yl]-2~{H}-indazol-6-yl]pyridine-3-carboxylic acid
C25 H28 N6 O4
CPVGTJFGSVAPTE-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.83α = 90
b = 64.58β = 102.29
c = 116.41γ = 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: 2017-12-20
    Type: Initial release
  • Version 1.1: 2018-01-17
    Changes: Database references
  • Version 1.2: 2018-01-31
    Changes: Database references