4ZYI

Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with cpd2

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.239 
  • R-Value Observed: 0.239 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

Holzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., Pissot-Soldermann, C., Rynn, C., Ruetz, S., Stutz, S., Chene, P., Jeay, S., Gessier, F.

(2015) J Med Chem 58: 6348-6358

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00810
  • Primary Citation of Related Structures:  
    4ZYF, 4ZYI

  • PubMed Abstract: 

    As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

    • Organizational Affiliation: 

    Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.


Macromolecules
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(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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4TH
Query on 4TH
Download Ideal Coordinates CCD File 
B [auth A](S)-7-((R)-sec-butoxy)-1-(4-chlorophenyl)-6-methoxy-2-(4-(methyl(pyridin-4-ylmethyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one
C33 H34 Cl N3 O3
RNOXGLRIZIHGIA-NBLPZQPVSA-N
CL
Query on CL
Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.239 
  • R-Value Observed: 0.239 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.748α = 90
b = 55.748β = 90
c = 107.324γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2015-07-29 
    • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-29
    Type: Initial release
  • Version 1.1: 2015-09-09
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description