5KE0

Discovery of 1-1H-Pyrazolo 4,3-c pyridine-6-yl urea Inhibitors of Extracellular Signal Regulated Kinase ERK for the Treatment of Cancers


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers.

Lim, J.Kelley, E.H.Methot, J.L.Zhou, H.Petrocchi, A.Chen, H.Hill, S.E.Hinton, M.C.Hruza, A.Jung, J.O.Maclean, J.K.Mansueto, M.Naumov, G.N.Philippar, U.Raut, S.Spacciapoli, P.Sun, D.Siliphaivanh, P.

(2016) J Med Chem 59: 6501-6511

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00708
  • Primary Citation of Related Structures:  
    5KE0

  • PubMed Abstract: 

    The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.


  • Organizational Affiliation

    Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1366Rattus norvegicusMutation(s): 0 
Gene Names: Mapk1Erk2MapkPrkm1
EC: 2.7.11.24
UniProt
Find proteins for P63086 (Rattus norvegicus)
Explore P63086 
Go to UniProtKB:  P63086
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63086
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.105α = 90
b = 91.334β = 90
c = 62.917γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
SCALAdata scaling
MOLREPphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-06
    Type: Initial release
  • Version 1.1: 2016-07-27
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references