4KZC

Structure of PI3K gamma with Imidazopyridine inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.25 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.235 
  • R-Value Observed: 0.236 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K.

Pecchi, S.Ni, Z.J.Han, W.Smith, A.Lan, J.Burger, M.Merritt, H.Wiesmann, M.Chan, J.Kaufman, S.Knapp, M.S.Janssen, J.Huh, K.Voliva, C.F.

(2013) Bioorg Med Chem Lett 23: 4652-4656

  • DOI: https://doi.org/10.1016/j.bmcl.2013.06.010
  • Primary Citation of Related Structures:  
    4KZ0, 4KZC

  • PubMed Abstract: 

    PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.


  • Organizational Affiliation

    Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform966Homo sapiensMutation(s): 1 
Gene Names: PIK3CG
EC: 2.7.1.153 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48736 (Homo sapiens)
Explore P48736 
Go to UniProtKB:  P48736
PHAROS:  P48736
GTEx:  ENSG00000105851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48736
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1UK
Query on 1UK

Download Ideal Coordinates CCD File 
B [auth A]N-{6-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[1,2-a]pyridin-2-yl}acetamide
C15 H12 F3 N5 O
TVUPSIBSWDXJGQ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
1UK BindingDB:  4KZC IC50: 8.2 (nM) from 1 assay(s)
PDBBind:  4KZC IC50: 8.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.25 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.235 
  • R-Value Observed: 0.236 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 146.383α = 90
b = 68.313β = 95.24
c = 108.161γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
TNTrefinement
PDB_EXTRACTdata extraction
BOSdata collection
XSCALEdata scaling
PHASERphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-07-17
    Type: Initial release
  • Version 1.1: 2013-08-28
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations