6QEI

CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR 5,6-Difluoro-3-(2-isopropoxy-4-piperazin-1-yl-phenyl)-1H-indole-2-carboxylic acid amide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors.

Heinrich, T.Seenisamy, J.Blume, B.Bomke, J.Calderini, M.Eckert, U.Friese-Hamim, M.Kohl, R.Lehmann, M.Leuthner, B.Musil, D.Rohdich, F.Zenke, F.T.

(2019) J Med Chem 62: 5025-5039

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00041
  • Primary Citation of Related Structures:  
    6QED, 6QEF, 6QEG, 6QEH, 6QEI, 6QEJ

  • PubMed Abstract: 

    Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC 50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC 50 of 1.9 μM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC 50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.


  • Organizational Affiliation

    Merck Healthcare, Merck KGaA , Frankfurter Str. 250 , 64293 Darmstadt , Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Methionine aminopeptidase 2378Homo sapiensMutation(s): 0 
Gene Names: METAP2MNPEPP67EIF2
EC: 3.4.11.18
UniProt & NIH Common Fund Data Resources
Find proteins for P50579 (Homo sapiens)
Explore P50579 
Go to UniProtKB:  P50579
PHAROS:  P50579
GTEx:  ENSG00000111142 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP50579
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HZE
Query on HZE

Download Ideal Coordinates CCD File 
F [auth A]5,6-bis(fluoranyl)-3-(4-piperazin-1-yl-2-propan-2-yloxy-phenyl)-1~{H}-indole-2-carboxamide
C22 H24 F2 N4 O2
VLTSNEYKDGRFDU-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
E [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.808α = 90
b = 99.784β = 90
c = 100.819γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-01
    Type: Initial release
  • Version 1.1: 2019-06-05
    Changes: Data collection, Database references
  • Version 1.2: 2024-05-15
    Changes: Data collection, Database references, Derived calculations