4O6E

Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine Inhibitors of Erk2

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2.

Blake, J.F., Gaudino, J.J., De Meese, J., Mohr, P., Chicarelli, M., Tian, H., Garrey, R., Thomas, A., Siedem, C.S., Welch, M.B., Kolakowski, G., Kaus, R., Burkard, M., Martinson, M., Chen, H., Dean, B., Dudley, D.A., Gould, S.E., Pacheco, P., Shahidi-Latham, S., Wang, W., West, K., Yin, J., Moffat, J., Schwarz, J.B.

(2014) Bioorg Med Chem Lett 24: 2635-2639

  • DOI: https://doi.org/10.1016/j.bmcl.2014.04.068
  • Primary Citation of Related Structures:  
    4O6E

  • PubMed Abstract: 

    The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.

    • Organizational Affiliation: 

    Array BioPharma Inc, Boulder, CO 80301, USA. Electronic address: jblake@arraybiopharma.com.


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: MAPK1, ERK2, PRKM1, PRKM2
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2SH
Query on 2SH
Download Ideal Coordinates CCD File 
B [auth A]N-[(1S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]-2-(tetrahydro-2H-pyran-4-ylamino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide
C21 H25 Cl F N5 O3
QTZUMCMRRPENJM-LJQANCHMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2SH BindingDB:  4O6E Ki: 0.4 (nM) from 1 assay(s)
IC50: min: 1, max: 45 (nM) from 2 assay(s)
Binding MOAD:  4O6E IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.85α = 90
b = 65.766β = 95
c = 52.654γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-05-21
    Type: Initial release
  • Version 1.1: 2014-06-25
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations