4G11

X-ray structure of PI3K-gamma bound to a 4-(morpholin-4-yl)- (6-oxo-1,6-dihydropyrimidin-2-yl)amide inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free: 0.349 
  • R-Value Work: 0.282 
  • R-Value Observed: 0.285 

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Ligand Structure Quality Assessment 


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


Literature

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3K beta inhibitors

Certal, V., Halley, F., Virone-Oddos, A., Thompson, F., Filoche-Romme, B., El-Ahmad, Y., Carry, J.C., Delorme, C., Karlsson, A., Abecassis, P.Y., Vincent, L., Bonnevaux, H., Nicolas, J.P., Morales, R., Michot, N., Vade, I., Louboutin, A., Perron, S., Doerflinger, G., Tric, B., Monget, S., Lengauer, C., Schio, L.

(2012) Bioorg Med Chem Lett 22: 6381-6384

  • DOI: https://doi.org/10.1016/j.bmcl.2012.08.072
  • Primary Citation of Related Structures:  
    4G11

  • PubMed Abstract: 

    From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.

    • Organizational Affiliation: 

    Medicinal Chemistry Oncology Drug Discovery, Sanofi, Vitry-sur-Seine, France.


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): 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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0W7
Query on 0W7
Download Ideal Coordinates CCD File 
B [auth A]2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide
C16 H18 N4 O3
FPFCFOIMTFHSNY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0W7 BindingDB:  4G11 IC50: 1.00e+4 (nM) from 1 assay(s)
PDBBind:  4G11 IC50: 1.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free: 0.349 
  • R-Value Work: 0.282 
  • R-Value Observed: 0.285 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 140.63α = 90
b = 67.38β = 96.14
c = 105.89γ = 90
Software Package:
Software NamePurpose
DNAdata collection
MOLREPphasing
REFMACrefinement
PROCESSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2012-11-14 
    • Deposition Author(s): Morales, R.

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-14
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description