3MJW

PI3 Kinase gamma with a benzofuranone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.87 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.225 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

5-Ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.

Zhang, N.Ayral-Kaloustian, S.Anderson, J.T.Nguyen, T.Das, S.Venkatesan, A.M.Brooijmans, N.Lucas, J.Yu, K.Hollander, I.Mallon, R.

(2010) Bioorg Med Chem Lett 20: 3526-3529

  • DOI: https://doi.org/10.1016/j.bmcl.2010.04.139
  • Primary Citation of Related Structures:  
    3MJW

  • PubMed Abstract: 

    A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.


  • Organizational Affiliation

    Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA. zhangn@wyeth.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 isoform966Homo sapiensMutation(s): 0 
Gene Names: PIK3CG
EC: 2.7.1.153
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
WYF
Query on WYF

Download Ideal Coordinates CCD File 
B [auth A](2Z)-4,6-dihydroxy-2-[(8-methoxy-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl)methylidene]-1-benzofuran-3(2H)-one
C21 H18 N2 O5
HUEDLQSVQCSQPS-OCKHKDLRSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.87 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.225 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 145.6α = 90
b = 68.573β = 95.02
c = 107.246γ = 90
Software Package:
Software NamePurpose
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-06-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description