3K5K

Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent Inhibitor of Histone Lysine Methyltransferase, G9a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.

Liu, F.Chen, X.Allali-Hassani, A.Quinn, A.M.Wasney, G.A.Dong, A.Barsyte, D.Kozieradzki, I.Senisterra, G.Chau, I.Siarheyeva, A.Kireev, D.B.Jadhav, A.Herold, J.M.Frye, S.V.Arrowsmith, C.H.Brown, P.J.Simeonov, A.Vedadi, M.Jin, J.

(2009) J Med Chem 52: 7950-7953

  • DOI: https://doi.org/10.1021/jm901543m
  • Primary Citation of Related Structures:  
    3K5K

  • PubMed Abstract: 

    SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.


  • Organizational Affiliation

    Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-lysine N-methyltransferase, H3 lysine-9 specific 3
A, B
283Homo sapiensMutation(s): 0 
Gene Names: EHMT2BAT8C6orf30G9AKMT1CNG36
EC: 2.1.1.43
UniProt & NIH Common Fund Data Resources
Find proteins for Q96KQ7 (Homo sapiens)
Explore Q96KQ7 
Go to UniProtKB:  Q96KQ7
PHAROS:  Q96KQ7
GTEx:  ENSG00000204371 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96KQ7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DXQ
Query on DXQ

Download Ideal Coordinates CCD File 
H [auth A],
Q [auth B]
7-[3-(dimethylamino)propoxy]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine
C26 H43 N7 O2
XIVUGRBSBIXXJE-UHFFFAOYSA-N
SAH
Query on SAH

Download Ideal Coordinates CCD File 
G [auth A],
P [auth B]
S-ADENOSYL-L-HOMOCYSTEINE
C14 H20 N6 O5 S
ZJUKTBDSGOFHSH-WFMPWKQPSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
L [auth B]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
L [auth B],
M [auth B],
N [auth B],
O [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
R [auth B],
S [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
UNX
Query on UNX

Download Ideal Coordinates CCD File 
K [auth A],
T [auth B]
UNKNOWN ATOM OR ION
X
Binding Affinity Annotations 
IDSourceBinding Affinity
SAH BindingDB:  3K5K Ki: 570 (nM) from 1 assay(s)
IC50: min: 1820, max: 4100 (nM) from 3 assay(s)
DXQ BindingDB:  3K5K Ki: 2.6 (nM) from 1 assay(s)
Kd: 23 (nM) from 1 assay(s)
IC50: min: 15, max: 5.70e+4 (nM) from 6 assay(s)
Binding MOAD:  3K5K Kd: 23 (nM) from 1 assay(s)
PDBBind:  3K5K Kd: 23 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.674α = 90
b = 78.074β = 91.81
c = 72.507γ = 90
Software Package:
Software NamePurpose
SBC-Collectdata collection
PHASERphasing
REFMACrefinement
Cootmodel building
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2009-11-10
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Advisory, Refinement description
  • Version 1.3: 2023-09-06
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description