6DAK

Discovery of Potent 2-Aryl-6,7-Dihydro-5HPyrrolo[ 1,2-a]imidazoles as WDR5 WIN-site Inhibitors Using Fragment-Based Methods and Structure-Based Design


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.159 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of Potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design.

Wang, F.Jeon, K.O.Salovich, J.M.Macdonald, J.D.Alvarado, J.Gogliotti, R.D.Phan, J.Olejniczak, E.T.Sun, Q.Wang, S.Camper, D.Yuh, J.P.Shaw, J.G.Sai, J.Rossanese, O.W.Tansey, W.P.Stauffer, S.R.Fesik, S.W.

(2018) J Med Chem 61: 5623-5642

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00375
  • Primary Citation of Related Structures:  
    6D9X, 6DAI, 6DAK, 6DAR, 6DAS

  • PubMed Abstract: 

    WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
WD repeat-containing protein 5313Homo sapiensMutation(s): 0 
Gene Names: WDR5BIG3
UniProt & NIH Common Fund Data Resources
Find proteins for P61964 (Homo sapiens)
Explore P61964 
Go to UniProtKB:  P61964
PHAROS:  P61964
GTEx:  ENSG00000196363 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61964
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
G1Y
Query on G1Y

Download Ideal Coordinates CCD File 
B [auth A]N-{[3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)phenyl]methyl}benzamide
C20 H19 N3 O
OHOWMSISBAWFED-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
C [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
G1Y BindingDB:  6DAK Ki: 7210 (nM) from 1 assay(s)
Binding MOAD:  6DAK Ki: 7210 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.159 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 80.969α = 90
b = 86.191β = 90
c = 40.528γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesWDR5-MLL1 NExT Leidos Biomedical Research 16X117 HHSN2162008000 01E UNIV 57992

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-05
    Type: Initial release
  • Version 1.1: 2018-10-31
    Changes: Data collection, Database references
  • Version 1.2: 2018-11-07
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description