5TRF

MDM2 in complex with SAR405838


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression.

Wang, S.Sun, W.Zhao, Y.McEachern, D.Meaux, I.Barriere, C.Stuckey, J.A.Meagher, J.L.Bai, L.Liu, L.Hoffman-Luca, C.G.Lu, J.Shangary, S.Yu, S.Bernard, D.Aguilar, A.Dos-Santos, O.Besret, L.Guerif, S.Pannier, P.Gorge-Bernat, D.Debussche, L.

(2014) Cancer Res 74: 5855-5865

  • DOI: https://doi.org/10.1158/0008-5472.CAN-14-0799
  • Primary Citation of Related Structures:  
    5TRF

  • PubMed Abstract: 

    Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.


  • Organizational Affiliation

    University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan. shaomeng@umich.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B, C, D, E
109Homo 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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7HC
Query on 7HC

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B],
N [auth C],
R [auth D],
S [auth E]
(2'S,3R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-N-(trans-4-hydroxycyclohexyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxamide
C29 H34 Cl2 F N3 O3
IDKAKZRYYDCJDU-HBMMIIHUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
G [auth A],
O [auth C],
T [auth E]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
H [auth A]
I [auth A]
J [auth A]
L [auth B]
M [auth B]
H [auth A],
I [auth A],
J [auth A],
L [auth B],
M [auth B],
P [auth C],
Q [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7HC Binding MOAD:  5TRF Ki: 0.88 (nM) from 1 assay(s)
BindingDB:  5TRF Ki: min: 0.88, max: 10 (nM) from 2 assay(s)
Kd: 2.7 (nM) from 1 assay(s)
IC50: 100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 138.849α = 90
b = 138.849β = 90
c = 83.707γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-09
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Derived calculations, Refinement description
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references