4DK5

Crystal structure of human PI3K-gamma in complex with a pyridyl-triazine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.95 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.224 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.

Smith, A.L.D'Angelo, N.D.Bo, Y.Y.Booker, S.K.Cee, V.J.Herberich, B.Hong, F.T.Jackson, C.L.Lanman, B.A.Liu, L.Nishimura, N.Pettus, L.H.Reed, A.B.Tadesse, S.Tamayo, N.A.Wurz, R.P.Yang, K.Andrews, K.L.Whittington, D.A.McCarter, J.D.Miguel, T.S.Zalameda, L.Jiang, J.Subramanian, R.Mullady, E.L.Caenepeel, S.Freeman, D.J.Wang, L.Zhang, N.Wu, T.Hughes, P.E.Norman, M.H.

(2012) J Med Chem 55: 5188-5219

  • DOI: https://doi.org/10.1021/jm300184s
  • Primary Citation of Related Structures:  
    4DK5

  • PubMed Abstract: 

    A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. adrians@amgen.com


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 isoform959Homo sapiensMutation(s): 0 
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
Binding Affinity Annotations 
IDSourceBinding Affinity
0KO PDBBind:  4DK5 Ki: 4 (nM) from 1 assay(s)
BindingDB:  4DK5 Ki: min: 4, max: 8 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.95 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.224 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 143.775α = 90
b = 68.233β = 94.99
c = 107.182γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-16
    Type: Initial release
  • Version 1.1: 2012-08-01
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description