6GL3

Crystal structure of human Phosphatidylinositol 4-kinase III beta (PI4KIIIbeta) in complex with ligand 44


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.77 Å
  • R-Value Free: 0.333 
  • R-Value Work: 0.276 
  • R-Value Observed: 0.278 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of a Potent, Orally Bioavailable PI4KIII beta Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo.

Reuberson, J.Horsley, H.Franklin, R.J.Ford, D.Neuss, J.Brookings, D.Huang, Q.Vanderhoydonck, B.Gao, L.J.Jang, M.Y.Herdewijn, P.Ghawalkar, A.Fallah-Arani, F.Khan, A.R.Henshall, J.Jairaj, M.Malcolm, S.Ward, E.Shuttleworth, L.Lin, Y.Li, S.Louat, T.Waer, M.Herman, J.Payne, A.Ceska, T.Doyle, C.Pitt, W.Calmiano, M.Augustin, M.Steinbacher, S.Lammens, A.Allen, R.

(2018) J Med Chem 61: 6705-6723

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00521
  • Primary Citation of Related Structures:  
    6GL3

  • PubMed Abstract: 

    The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.


  • Organizational Affiliation

    UCB Pharma , 208 Bath Road , Slough , Berkshire SL1 3WE , United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 4-kinase beta,Phosphatidylinositol 4-kinase beta
A, B
386Homo sapiensMutation(s): 0 
Gene Names: PI4KBPIK4CB
EC: 2.7.1.67
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UBF8 (Homo sapiens)
Explore Q9UBF8 
Go to UniProtKB:  Q9UBF8
PHAROS:  Q9UBF8
GTEx:  ENSG00000143393 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UBF8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EMW
Query on EMW

Download Ideal Coordinates CCD File 
C [auth A](3~{S})-4-(6-azanyl-1-methyl-pyrazolo[3,4-d]pyrimidin-4-yl)-~{N}-(4-methoxy-2-methyl-phenyl)-3-methyl-piperazine-1-carboxamide
C20 H26 N8 O2
WRONAJQPZWDYAR-ZDUSSCGKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EMW BindingDB:  6GL3 IC50: min: 5, max: 37 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.77 Å
  • R-Value Free: 0.333 
  • R-Value Work: 0.276 
  • R-Value Observed: 0.278 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.468α = 90
b = 69.484β = 90
c = 172.84γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-15
    Type: Initial release
  • Version 1.1: 2018-08-22
    Changes: Data collection, Database references