5O7I

ERK5 in complex with a pyrrole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38 alpha and BRD4.

Myers, S.M.Miller, D.C.Molyneux, L.Arasta, M.Bawn, R.H.Blackburn, T.J.Cook, S.J.Edwards, N.Endicott, J.A.Golding, B.T.Griffin, R.J.Hammonds, T.Hardcastle, I.R.Harnor, S.J.Heptinstall, A.B.Lochhead, P.A.Martin, M.P.Martin, N.C.Newell, D.R.Owen, P.J.Pang, L.C.Reuillon, T.Rigoreau, L.J.M.Thomas, H.D.Tucker, J.A.Wang, L.Z.Wong, A.C.Noble, M.E.M.Wedge, S.R.Cano, C.

(2019) Eur J Med Chem 178: 530-543

  • DOI: https://doi.org/10.1016/j.ejmech.2019.05.057
  • Primary Citation of Related Structures:  
    5LRQ, 5O7I

  • PubMed Abstract: 

    Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC 50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC 50 0.82 μM for ERK5; IC 50  > 120 μM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.


  • Organizational Affiliation

    Newcastle Drug Discovery, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 7358Homo sapiensMutation(s): 0 
Gene Names: MAPK7BMK1ERK5PRKM7
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q13164 (Homo sapiens)
Explore Q13164 
Go to UniProtKB:  Q13164
PHAROS:  Q13164
GTEx:  ENSG00000166484 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13164
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9N8 (Subject of Investigation/LOI)
Query on 9N8

Download Ideal Coordinates CCD File 
B [auth A]4-(2-bromanyl-6-fluoranyl-phenyl)carbonyl-~{N}-pyridin-3-yl-1~{H}-pyrrole-2-carboxamide
C17 H11 Br F N3 O2
ATKCERYALDNMPL-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
9N8 BindingDB:  5O7I IC50: min: 820, max: 3000 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.91α = 90
b = 93.91β = 90
c = 113.748γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (United Kingdom)United KingdomRES/0190/7680

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-20
    Type: Initial release
  • Version 1.1: 2019-06-05
    Changes: Data collection, Database references
  • Version 1.2: 2019-06-26
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description