4ACM

CDK2 IN COMPLEX WITH 3-AMINO-6-(4-{[2-(DIMETHYLAMINO)ETHYL]SULFAMOYL}-PHENYL)-N-PYRIDIN-3-YLPYRAZINE-2-CARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of novel potent and highly selective glycogen synthase kinase-3 beta (GSK3 beta ) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.

Berg, S.Bergh, M.Hellberg, S.Hogdin, K.Lo-Alfredsson, Y.Soderman, P.von Berg, S.Weigelt, T.Ormo, M.Xue, Y.Tucker, J.Neelissen, J.Jerning, E.Nilsson, Y.Bhat, R.

(2012) J Med Chem 55: 9107-9119

  • DOI: https://doi.org/10.1021/jm201724m
  • Primary Citation of Related Structures:  
    4ACC, 4ACD, 4ACG, 4ACH, 4ACM

  • PubMed Abstract: 

    Glycogen synthase kinase-3β, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3β localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.


  • Organizational Affiliation

    Department of Medicinal Chemistry, AstraZeneca R&D, Innovative Medicines CNS & Pain Södertälje, SE-151 85 Södertälje, Sweden. Stefan.berg@astrazeneca.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 2299Homo sapiensMutation(s): 0 
EC: 2.7.11.22
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7YG
Query on 7YG

Download Ideal Coordinates CCD File 
D [auth A]3-AMINO-6-(4-{[2-(DIMETHYLAMINO)ETHYL]SULFAMOYL}PHENYL)-N-PYRIDIN-3-YLPYRAZINE-2-CARBOXAMIDE
C20 H23 N7 O3 S
HULMMZPBCUBDJN-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7YG Binding MOAD:  4ACM Ki: 210 (nM) from 1 assay(s)
PDBBind:  4ACM Ki: 210 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.43α = 90
b = 71.81β = 90
c = 72.04γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-16
    Type: Initial release
  • Version 1.1: 2012-11-21
    Changes: Database references
  • Version 1.2: 2018-02-14
    Changes: Database references, Structure summary