3LJ3

PI3-kinase-gamma with a pyrrolopyridine-benzofuran inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.224 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).

Tsou, H.R., MacEwan, G., Birnberg, G., Grosu, G., Bursavich, M.G., Bard, J., Brooijmans, N., Toral-Barza, L., Hollander, I., Mansour, T.S., Ayral-Kaloustian, S., Yu, K.

(2010) Bioorg Med Chem Lett 20: 2321-2325

  • DOI: https://doi.org/10.1016/j.bmcl.2010.01.135
  • Primary Citation of Related Structures:  
    3LJ3

  • PubMed Abstract: 

    We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.

    • Organizational Affiliation: 

    Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. tsouh@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): 1 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
WYE
Query on WYE
Download Ideal Coordinates CCD File 
D [auth A](2Z)-4,6-dihydroxy-2-{[1-methyl-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methylidene}-1-benzofuran-3(2H)-one
C22 H22 N4 O4
RLZIWQDVHJTWEF-NVMNQCDNSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]		SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
WYE PDBBind:  3LJ3 IC50: 0.94 (nM) from 1 assay(s)
Binding MOAD:  3LJ3 IC50: 43 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.224 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 145.071α = 90
b = 68.509β = 94.64
c = 106.692γ = 90
Software Package:
Software NamePurpose
PHENIXmodel building
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-04-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-02-29
    Changes: Derived calculations
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description