6G9H

Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Heightman, T.D.Berdini, V.Braithwaite, H.Buck, I.M.Cassidy, M.Castro, J.Courtin, A.Day, J.E.H.East, C.Fazal, L.Graham, B.Griffiths-Jones, C.M.Lyons, J.F.Martins, V.Muench, S.Munck, J.M.Norton, D.O'Reilly, M.Palmer, N.Pathuri, P.Reader, M.Rees, D.C.Rich, S.J.Richardson, C.Saini, H.Thompson, N.T.Wallis, N.G.Walton, H.Wilsher, N.E.Woolford, A.J.Cooke, M.Cousin, D.Onions, S.Shannon, J.Watts, J.Murray, C.W.

(2018) J Med Chem 61: 4978-4992

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00421
  • Primary Citation of Related Structures:  
    6G8X, 6G91, 6G92, 6G93, 6G97, 6G9A, 6G9D, 6G9H, 6G9J, 6G9K, 6G9M, 6G9N, 6GDM, 6GDQ, 6GE0

  • PubMed Abstract: 

    Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.


  • Organizational Affiliation

    Astex Pharmaceuticals , 436 Cambridge Science Park , Cambridge , CB4 0QA , U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1368Homo sapiensMutation(s): 0 
Gene Names: MAPK1ERK2PRKM1PRKM2
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for P28482 (Homo sapiens)
Explore P28482 
Go to UniProtKB:  P28482
PHAROS:  P28482
GTEx:  ENSG00000100030 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28482
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
ERW BindingDB:  6G9H IC50: min: 3, max: 630 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.914α = 90
b = 70.673β = 110.31
c = 60.884γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2018-05-30 
  • Deposition Author(s): O'Reilly, M.

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-30
    Type: Initial release
  • Version 1.1: 2018-06-13
    Changes: Data collection, Database references
  • Version 1.2: 2018-06-27
    Changes: Data collection, Database references
  • Version 1.3: 2024-11-20
    Changes: Data collection, Database references, Structure summary