5W4W | pdb_00005w4w

Identification and Profiling of a Selective and Brain Penetrant Radioligand for In Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 
    0.215 (Depositor), 0.230 (DCC) 
  • R-Value Work: 
    0.180 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 
    0.181 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 9WGClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors.

Wager, T.T.Galatsis, P.Chandrasekaran, R.Y.Butler, T.W.Li, J.Zhang, L.Mente, S.Subramanyam, C.Liu, S.Doran, A.C.Chang, C.Fisher, K.Grimwood, S.Hedde, J.R.Marconi, M.Schildknegt, K.

(2017) ACS Chem Neurosci 8: 1995-2004

  • DOI: https://doi.org/10.1021/acschemneuro.7b00155
  • Primary Citation of Related Structures:  
    5W4W

  • PubMed Abstract: 

    To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [ 3 H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [ 3 H]-9 to determine the binding affinity for PF-670462, a literature CK1δ/ε inhibitor tool compound. Lastly, [ 3 H]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1δ/ε in vivo pharmacology (circadian rhythm modulation).


  • Organizational Affiliation

    Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 1 Portland, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase I isoform delta
A, B, C, D
331Homo sapiensMutation(s): 0 
Gene Names: CSNK1DHCKID
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.26 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48730 (Homo sapiens)
Explore P48730 
Go to UniProtKB:  P48730
PHAROS:  P48730
GTEx:  ENSG00000141551 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48730
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9WG
Query on 9WG

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
P [auth C],
U [auth D]
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one
C18 H15 F N4 O
NGDXEOHYWJHBTJ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
J [auth B]
K [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
9WG BindingDB:  5W4W IC50: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free:  0.215 (Depositor), 0.230 (DCC) 
  • R-Value Work:  0.180 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 0.181 (Depositor) 
Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.884α = 70.37
b = 84.584β = 74.27
c = 89.042γ = 86.77
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 9WGClick on this verticalbar to view details

Entry History 

Deposition Data

  • Released Date: 2017-06-28 
  • Deposition Author(s): Liu, S.

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-28
    Type: Initial release
  • Version 1.1: 2017-10-04
    Changes: Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references