5IU2

Discovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.234 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.

Glatthar, R.Stojanovic, A.Troxler, T.Mattes, H.Mobitz, H.Beerli, R.Blanz, J.Gassmann, E.Druckes, P.Fendrich, G.Gutmann, S.Martiny-Baron, G.Spence, F.Hornfeld, J.Peel, J.E.Sparrer, H.

(2016) J Med Chem 59: 7544-7560

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00598
  • Primary Citation of Related Structures:  
    5IU2

  • PubMed Abstract: 

    Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.


  • Organizational Affiliation

    Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase kinase kinase 8
A, B
332Homo sapiensMutation(s): 0 
EC: 2.7.11.25
UniProt & NIH Common Fund Data Resources
Find proteins for P41279 (Homo sapiens)
Explore P41279 
Go to UniProtKB:  P41279
PHAROS:  P41279
GTEx:  ENSG00000107968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP41279
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6DA
Query on 6DA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-[2-(morpholin-4-yl)ethyl]-6-(8-phenyl-1H-imidazo[4,5-c][1,7]naphthyridin-1-yl)-1,3-benzothiazol-2-amine
C28 H25 N7 O S
WJOPLUBIUOVUKG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6DA BindingDB:  5IU2 IC50: min: 16, max: 2500 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.234 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.48α = 90
b = 87.43β = 90
c = 125.12γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-24
    Type: Initial release
  • Version 1.1: 2016-09-07
    Changes: Database references
  • Version 1.2: 2024-02-07
    Changes: Data collection, Database references, Refinement description