5OC8

HDM2 (17-111, WILD TYPE) COMPLEXED WITH NVP-HDM201 AT 1.56A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.237 
  • R-Value Observed: 0.238 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53-MDM2 Inhibitor HDM201.

Jeay, S.Ferretti, S.Holzer, P.Fuchs, J.Chapeau, E.A.Wartmann, M.Sterker, D.Romanet, V.Murakami, M.Kerr, G.Durand, E.Y.Gaulis, S.Cortes-Cros, M.Ruetz, S.Stachyra, T.M.Kallen, J.Furet, P.Wurthner, J.Guerreiro, N.Halilovic, E.Jullion, A.Kauffmann, A.Kuriakose, E.Wiesmann, M.Jensen, M.R.Hofmann, F.Sellers, W.R.

(2018) Cancer Res 78: 6257-6267

  • DOI: https://doi.org/10.1158/0008-5472.CAN-18-0338
  • Primary Citation of Related Structures:  
    5OC8

  • PubMed Abstract: 

    Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro , and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2-p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure-response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53-MDM2 inhibitors. Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257-67. ©2018 AACR .


  • Organizational Affiliation

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.


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: 2.3.2.27
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9QW
Query on 9QW

Download Ideal Coordinates CCD File 
B [auth A](4~{S})-5-(5-chloranyl-1-methyl-2-oxidanylidene-pyridin-3-yl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-d]imidazol-6-one
C26 H24 Cl2 N6 O4
AGBSXNCBIWWLHD-FQEVSTJZSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
9QW BindingDB:  5OC8 Ki: 0.21 (nM) from 1 assay(s)
IC50: min: 0.23, max: 0.34 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.237 
  • R-Value Observed: 0.238 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.406α = 90
b = 56.406β = 90
c = 104.913γ = 120
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2018-08-22 
  • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-22
    Type: Initial release
  • Version 1.1: 2018-09-05
    Changes: Data collection, Database references
  • Version 1.2: 2018-11-14
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description