4JPS

Co-crystal Structures of the Lipid Kinase PI3K alpha with Pan and Isoform Selective Inhibitors

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation.

Furet, P., Guagnano, V., Fairhurst, R.A., Imbach-Weese, P., Bruce, I., Knapp, M., Fritsch, C., Blasco, F., Blanz, J., Aichholz, R., Hamon, J., Fabbro, D., Caravatti, G.

(2013) Bioorg Med Chem Lett 23: 3741-3748

  • DOI: https://doi.org/10.1016/j.bmcl.2013.05.007
  • Primary Citation of Related Structures:  
    4JPS

  • PubMed Abstract: 

    Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compounds in inhibiting PI3Kα, a medicinal chemistry program has led to the discovery of the clinical candidate NVP-BYL719.

    • Organizational Affiliation: 

    Novartis Institutes for BioMedical Research, WKL-136.4.12, CH-4002 Basel, Switzerland.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform1,074Homo sapiensMutation(s): 2 
Gene Names: PIK3CA
EC: 2.7.1.153 (PDB Primary Data), 2.7.11.1 (PDB Primary Data), 2.7.1.137 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P42336 (Homo sapiens)
Explore P42336 
Go to UniProtKB:  P42336
PHAROS:  P42336
GTEx:  ENSG00000121879 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42336
Sequence Annotations
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  • Reference Sequence
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 3-kinase regulatory subunit alpha293Homo sapiensMutation(s): 0 
Gene Names: GRB1, PIK3R1
UniProt & NIH Common Fund Data Resources
Find proteins for P27986 (Homo sapiens)
Explore P27986 
Go to UniProtKB:  P27986
PHAROS:  P27986
GTEx:  ENSG00000145675 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27986
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1LT
Query on 1LT
Download Ideal Coordinates CCD File 
D [auth A](2S)-N~1~-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}pyrrolidine-1,2-dicarboxamide
C19 H22 F3 N5 O2 S
STUWGJZDJHPWGZ-LBPRGKRZSA-N
SCN
Query on SCN
Download Ideal Coordinates CCD File 
C [auth A]THIOCYANATE ION
C N S
ZMZDMBWJUHKJPS-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
1LT BindingDB:  4JPS IC50: min: 3.9, max: 1837 (nM) from 11 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.865α = 90
b = 106.195β = 90
c = 133.667γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
CBASSdata collection
XSCALEdata scaling
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-02
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2022-10-12
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.3: 2024-05-22
    Changes: Data collection