3DBS

Structure of PI3K gamma in complex with GDC0941

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 

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Literature

The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer

Folkes, A.J., Ahmadi, K., Alderton, W.K., Alix, S., Baker, S.J., Box, G., Chuckowree, I.S., Clarke, P.A., Depledge, P., Eccles, S.A., Friedman, L.S., Hayes, A., Hancox, T.C., Kugendradas, A., Lensun, L., Moore, P., Olivero, A.G., Pang, J., Patel, S., Pergl-Wilson, G.H., Raynaud, F.I., Robson, A., Saghir, N., Salphati, L., Sohal, S., Ultsch, M.H., Valenti, M., Wallweber, H.J.A., Wan, N.C., Wiesmann, C., Workman, P., Zhyvoloup, A., Zvelebil, M.J., Shuttleworth, S.J.

(2008) J Med Chem 51: 5522-5532

  • DOI: https://doi.org/10.1021/jm800295d
  • Primary Citation of Related Structures:  
    3DBS

  • PubMed Abstract: 

    Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.

    • Organizational Affiliation: 

    Piramed Pharma, 957 Buckingham Avenue, Slough, Berks SL1 4NL, United Kingdom. adrian.folkes@piramed.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 isoform960Homo sapiensMutation(s): 0 
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
GD9
Query on GD9
Download Ideal Coordinates CCD File 
B [auth A]2-(1H-indazol-4-yl)-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
C23 H27 N7 O3 S2
LHNIIDJUOCFXAP-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
GD9 BindingDB:  3DBS Ki: min: 1.4, max: 41.8 (nM) from 3 assay(s)
Kd: min: 7.7, max: 48 (nM) from 2 assay(s)
IC50: min: 13, max: 746 (nM) from 10 assay(s)
PDBBind:  3DBS IC50: 75 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 144.284α = 90
b = 67.762β = 95.31
c = 106.972γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing

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: 2008-06-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description