4OGV

Co-Crystal Structure of MDM2 with Inhibitor Compound 49


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.256 
  • R-Value Observed: 0.257 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres.

Gonzalez, A.Z.Li, Z.Beck, H.P.Canon, J.Chen, A.Chow, D.Duquette, J.Eksterowicz, J.Fox, B.M.Fu, J.Huang, X.Houze, J.Jin, L.Li, Y.Ling, Y.Lo, M.C.Long, A.M.McGee, L.R.McIntosh, J.Oliner, J.D.Osgood, T.Rew, Y.Saiki, A.Y.Shaffer, P.Wortman, S.Yakowec, P.Yan, X.Ye, Q.Yu, D.Zhao, X.Zhou, J.Olson, S.H.Sun, D.Medina, J.C.

(2014) J Med Chem 57: 2963-2988

  • DOI: https://doi.org/10.1021/jm401911v
  • Primary Citation of Related Structures:  
    4OCC, 4ODE, 4ODF, 4OGN, 4OGT, 4OGV

  • PubMed Abstract: 

    We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.


  • Organizational Affiliation

    Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B, C
95Homo sapiensMutation(s): 0 
Gene Names: MDM2
EC: 6.3.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q00987 (Homo sapiens)
Explore Q00987 
Go to UniProtKB:  Q00987
PHAROS:  Q00987
GTEx:  ENSG00000135679 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00987
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2U7
Query on 2U7

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
[(2S,5R,6R)-4-[(2S)-1-(tert-butylsulfonyl)butan-2-yl]-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl]acetic acid
C26 H31 Cl2 N O6 S
UQONPZNBMIQADI-NEUULRRLSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2U7 BindingDB:  4OGV IC50: 9 (nM) from 1 assay(s)
Binding MOAD:  4OGV IC50: 9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.256 
  • R-Value Observed: 0.257 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.301α = 90
b = 97.412β = 90
c = 105.129γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-02
    Type: Initial release
  • Version 1.1: 2014-06-18
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description