6FTN

mPI3Kd IN COMPLEX WITH AZ2

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.248 
  • R-Value Observed: 0.249 

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This is version 1.1 of the entry. See complete history. 


Literature

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-gamma Inhibitors.

Pemberton, N., Mogemark, M., Arlbrandt, S., Bold, P., Cox, R.J., Gardelli, C., Holden, N.S., Karabelas, K., Karlsson, J., Lever, S., Li, X., Lindmark, H., Norberg, M., Perry, M.W.D., Petersen, J., Rodrigo Blomqvist, S., Thomas, M., Tyrchan, C., Westin Eriksson, A., Zlatoidsky, P., Oster, L.

(2018) J Med Chem 61: 5435-5441

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00447
  • Primary Citation of Related Structures:  
    6FTN

  • PubMed Abstract: 

    In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

    • Organizational Affiliation: 

    Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA , Beijing 100176 , P. R. China.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphor inositol 3 kinase939Mus musculusMutation(s): 0 
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
E78
Query on E78
Download Ideal Coordinates CCD File 
B [auth A]~{N}-[5-[2-[(1~{S})-1-cyclopropylethyl]-7-methyl-1-oxidanylidene-3~{H}-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl]ethanamide
C20 H23 N3 O2 S
CNCRCDLWUGCPSJ-LBPRGKRZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
E78 Binding MOAD:  6FTN IC50: 200 (nM) from 1 assay(s)
BindingDB:  6FTN IC50: min: 200, max: 1780 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.248 
  • R-Value Observed: 0.249 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.227α = 90
b = 65.012β = 103.38
c = 116.341γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2018-06-20 
    • Deposition Author(s): Petersen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-20
    Type: Initial release
  • Version 1.1: 2018-07-11
    Changes: Data collection, Database references