6N3N

Identification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.01 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.219 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.

Fujimoto, J.Kurasawa, O.Takagi, T.Liu, X.Banno, H.Kojima, T.Asano, Y.Nakamura, A.Nambu, T.Hata, A.Ishii, T.Sameshima, T.Debori, Y.Miyamoto, M.Klein, M.G.Tjhen, R.Sang, B.C.Levin, I.Lane, S.W.Snell, G.P.Li, K.Kefala, G.Hoffman, I.D.Ding, S.C.Cary, D.R.Mizojiri, R.

(2019) ACS Med Chem Lett 10: 1498-1503

  • DOI: https://doi.org/10.1021/acsmedchemlett.9b00400
  • Primary Citation of Related Structures:  
    6N3L, 6N3N, 6N3O

  • PubMed Abstract: 

    General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modification of the substructure of sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to the αC-helix allosteric pocket of GCN2 led to significant enhancement in potency and a good pharmacokinetic profile in mice. In addition, compound 6d , which showed slow dissociation in binding on GCN2, demonstrated antiproliferative activity in combination with the asparagine-depleting agent asparaginase in an acute lymphoblastic leukemia (ALL) cell line, and it also displayed suppression of GCN2 pathway activation with asparaginase treatment in the ALL cell line and mouse xenograft model.


  • Organizational Affiliation

    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2317Homo sapiensMutation(s): 4 
Gene Names: EIF2AK4GCN2KIAA1338
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9P2K8 (Homo sapiens)
Explore Q9P2K8 
Go to UniProtKB:  Q9P2K8
PHAROS:  Q9P2K8
GTEx:  ENSG00000128829 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9P2K8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KA4 (Subject of Investigation/LOI)
Query on KA4

Download Ideal Coordinates CCD File 
B [auth A]N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-2,5-dichloro-3-(hydroxymethyl)benzene-1-sulfonamide
C19 H12 Cl2 F2 N4 O3 S
VJXAWOQPYMAEFQ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.01 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.219 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.117α = 90
b = 82.117β = 90
c = 192.551γ = 120
Software Package:
Software NamePurpose
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-10-09
    Type: Initial release
  • Version 1.1: 2019-10-30
    Changes: Data collection, Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references