5IS5

Discovery and Pharmacological Characterization of Novel Quinazoline-based PI3K delta-selective Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.229 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

Hoegenauer, K.Soldermann, N.Stauffer, F.Furet, P.Graveleau, N.Smith, A.B.Hebach, C.Hollingworth, G.J.Lewis, I.Gutmann, S.Rummel, G.Knapp, M.Wolf, R.M.Blanz, J.Feifel, R.Burkhart, C.Zecri, F.

(2016) ACS Med Chem Lett 7: 762-767

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00119
  • Primary Citation of Related Structures:  
    5IS5, 5ITD

  • PubMed Abstract: 

    Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.


  • Organizational Affiliation

    Global Discovery Chemistry, Center for Proteomic Chemistry, Metabolism and Pharmacokinetics, Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research , Novartis Campus, 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 delta isoform1,044Mus 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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6CY
Query on 6CY

Download Ideal Coordinates CCD File 
B [auth A]5-{4-[3-(4-acetylpiperazine-1-carbonyl)phenyl]quinazolin-6-yl}-2-methoxypyridine-3-carbonitrile
C28 H24 N6 O3
QYTXJLQBSYAMGR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6CY BindingDB:  5IS5 IC50: min: 7, max: 125 (nM) from 10 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.229 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.46α = 90
b = 64.32β = 103.2
c = 116.64γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-10
    Type: Initial release
  • Version 1.1: 2016-09-14
    Changes: Database references
  • Version 1.2: 2017-01-18
    Changes: Data collection
  • Version 1.3: 2019-04-24
    Changes: Data collection, Source and taxonomy
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Refinement description