3QK0

Crystal structure of PI3K-gamma in complex with benzothiazole 82


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.229 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors.

D'Angelo, N.D.Kim, T.S.Andrews, K.Booker, S.K.Caenepeel, S.Chen, K.D'Amico, D.Freeman, D.Jiang, J.Liu, L.McCarter, J.D.San Miguel, T.Mullady, E.L.Schrag, M.Subramanian, R.Tang, J.Wahl, R.C.Wang, L.Whittington, D.A.Wu, T.Xi, N.Xu, Y.Yakowec, P.Yang, K.Zalameda, L.P.Zhang, N.Hughes, P.Norman, M.H.

(2011) J Med Chem 54: 1789-1811

  • DOI: https://doi.org/10.1021/jm1014605
  • Primary Citation of Related Structures:  
    3QJZ, 3QK0

  • PubMed Abstract: 

    Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. dangelo@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 isoform960Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
QK0 BindingDB:  3QK0 Ki: 4.7 (nM) from 1 assay(s)
PDBBind:  3QK0 Ki: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.229 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 144.525α = 90
b = 67.835β = 95.34
c = 107.096γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
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: 2011-03-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description