5LN2

Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.216 

Starting Model: experimental
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Ligand Structure Quality Assessment 


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Literature

Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.

Furet, P.Masuya, K.Kallen, J.Stachyra-Valat, T.Ruetz, S.Guagnano, V.Holzer, P.Mah, R.Stutz, S.Vaupel, A.Chene, P.Jeay, S.Schlapbach, A.

(2016) Bioorg Med Chem Lett 26: 4837-4841

  • DOI: https://doi.org/10.1016/j.bmcl.2016.08.010
  • Primary Citation of Related Structures:  
    5LN2

  • PubMed Abstract: 

    The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland. Electronic address: [email protected].


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 (PDB Primary Data), 2.3.2.27 (UniProt)
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
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6ZT
Query on 6ZT

Download Ideal Coordinates CCD File 
B [auth A](4~{S})-5-[5-chloranyl-2-[2-(dimethylamino)ethoxy]phenyl]-4-(4-chloranyl-2-methyl-phenyl)-2-(2-methoxyphenyl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-c]pyrazol-6-one
C32 H34 Cl2 N4 O3
YBMQYNARIZUNIO-HKBQPEDESA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.216 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.54α = 90
b = 56.54β = 90
c = 103.953γ = 120
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-09-07 
  • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-07
    Type: Initial release
  • Version 1.1: 2016-09-21
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description