4JV9

Co-crystal structure of MDM2 with inhibitor (2S,5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.240 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.

Gonzalez-Lopez de Turiso, F.Sun, D.Rew, Y.Bartberger, M.D.Beck, H.P.Canon, J.Chen, A.Chow, D.Correll, T.L.Huang, X.Julian, L.D.Kayser, F.Lo, M.C.Long, A.M.McMinn, D.Oliner, J.D.Osgood, T.Powers, J.P.Saiki, A.Y.Schneider, S.Shaffer, P.Xiao, S.H.Yakowec, P.Yan, X.Ye, Q.Yu, D.Zhao, X.Zhou, J.Medina, J.C.Olson, S.H.

(2013) J Med Chem 56: 4053-4070

  • DOI: https://doi.org/10.1021/jm400293z
  • Primary Citation of Related Structures:  
    4JV7, 4JV9, 4JVE, 4JVR, 4JWR

  • PubMed Abstract: 

    Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.


  • Organizational Affiliation

    Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm296Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
1MO PDBBind:  4JV9 IC50: 1800 (nM) from 1 assay(s)
Binding MOAD:  4JV9 IC50: 1800 (nM) from 1 assay(s)
BindingDB:  4JV9 IC50: 1800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.240 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.848α = 90
b = 59.848β = 90
c = 75.248γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-01
    Type: Initial release
  • Version 1.1: 2013-06-05
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations