4FHJ

Crystal Structure of PI3K-gamma in Complex with Imidazopyridine 2

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

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


Literature

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.

Peterson, E.A., Boezio, A.A., Andrews, P.S., Boezio, C.M., Bush, T.L., Cheng, A.C., Choquette, D., Coats, J.R., Colletti, A.E., Copeland, K.W., Dupont, M., Graceffa, R., Grubinska, B., Kim, J.L., Lewis, R.T., Liu, J., Mullady, E.L., Potashman, M.H., Romero, K., Shaffer, P.L., Stanton, M.K., Stellwagen, J.C., Teffera, Y., Yi, S., Cai, T., La, D.S.

(2012) Bioorg Med Chem Lett 22: 4967-4974

  • DOI: https://doi.org/10.1016/j.bmcl.2012.06.033
  • Primary Citation of Related Structures:  
    4FHJ, 4FHK

  • PubMed Abstract: 

    mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

    • Organizational Affiliation: 

    Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. epeterso@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 (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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 143.442α = 90
b = 67.3β = 95.67
c = 106.039γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction

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: 2012-07-18
    Type: Initial release
  • Version 1.1: 2012-08-29
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description