6IZQ

PRMT4 bound with a bicyclic compound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.

Guo, Z.Zhang, Z.Yang, H.Cao, D.Xu, X.Zheng, X.Chen, D.Wang, Q.Li, Y.Li, J.Du, Z.Wang, X.Chen, L.Ding, J.Shen, J.Geng, M.Huang, X.Xiong, B.

(2019) J Med Chem 62: 5414-5433

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00297
  • Primary Citation of Related Structures:  
    6IZQ

  • PubMed Abstract: 

    PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.


  • Organizational Affiliation

    Department of Medicinal Chemistry , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-arginine methyltransferase CARM1
A, B, C, D
333Homo sapiensMutation(s): 0 
Gene Names: CARM1PRMT4
EC: 2.1.1.319
UniProt & NIH Common Fund Data Resources
Find proteins for Q86X55 (Homo sapiens)
Explore Q86X55 
Go to UniProtKB:  Q86X55
PHAROS:  Q86X55
GTEx:  ENSG00000142453 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86X55
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
XJ2
Query on XJ2

Download Ideal Coordinates CCD File 
E [auth A](2R)-1-(methylamino)-3-(1,3,4,5-tetrahydro-2-benzazepin-2-yl)propan-2-ol
C14 H22 N2 O
YEILCWAUDAOYQR-CQSZACIVSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
XJ2 Binding MOAD:  6IZQ IC50: 3190 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.788α = 90
b = 98.926β = 90
c = 206.792γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
HKL-3000phasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-25
    Type: Initial release
  • Version 1.1: 2024-03-27
    Changes: Data collection, Database references