3W69

Crystal structure of human mdm2 with a dihydroimidazothiazole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.210 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors

Miyazaki, M.Naito, H.Sugimoto, Y.Yoshida, K.Kawato, H.Okayama, T.Shimizu, H.Miyazaki, M.Kitagawa, M.Seki, T.Fukutake, S.Shiose, Y.Aonuma, M.Soga, T.

(2013) Bioorg Med Chem 21: 4319-4331

  • DOI: https://doi.org/10.1016/j.bmc.2013.04.056
  • Primary Citation of Related Structures:  
    3W69

  • PubMed Abstract: 

    We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.


  • Organizational Affiliation

    Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. miyazaki.masaki.p3@daiichisankyo.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B
87Homo sapiensMutation(s): 1 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LTZ
Query on LTZ

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
(5R,6S)-2-[((2S,5R)-2-{[(3R)-4-acetyl-3-methylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidin-1-yl)carbonyl]-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole
C36 H43 Cl2 N5 O3 S
NYMONQQQYOURJF-GTVZXTIFSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B],
G [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
LTZ PDBBind:  3W69 IC50: 58 (nM) from 1 assay(s)
Binding MOAD:  3W69 IC50: 58 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.210 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.562α = 90
b = 65.761β = 90
c = 81.436γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
PROCESSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-05
    Type: Initial release
  • Version 1.1: 2014-04-30
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description