6DGT

Selective PI3K beta inhibitor bound to PI3K delta


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.318 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.237 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) beta Inhibitor.

Chandrasekhar, J.Dick, R.Van Veldhuizen, J.Koditek, D.Lepist, E.I.McGrath, M.E.Patel, L.Phillips, G.Sedillo, K.Somoza, J.R.Therrien, J.Till, N.A.Treiberg, J.Villasenor, A.G.Zherebina, Y.Perreault, S.

(2018) J Med Chem 61: 6858-6868

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00797
  • Primary Citation of Related Structures:  
    6DGT

  • PubMed Abstract: 

    Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.


  • Organizational Affiliation

    Gilead Sciences, Inc. , 199 East Blaine Street , Seattle , Washington 98102 , United States.


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 isoform938Mus musculusMutation(s): 0 
Gene Names: Pik3cd
EC: 2.7.1.153
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
GFJ
Query on GFJ

Download Ideal Coordinates CCD File 
B [auth A]4-[1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzimidazol-6-yl]-3-fluoropyridin-2-amine
C24 H15 F3 N8
SBVBUGSOYHJGGD-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.318 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.237 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.517α = 90
b = 143.502β = 90
c = 221.256γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-01
    Type: Initial release
  • Version 1.1: 2018-08-22
    Changes: Data collection, Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references