compound 29 [Moslin et al., 2017]   Click here for help

GtoPdb Ligand ID: 9992

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Compound 29 binds to the JH2 pseudokinase domain of the Janus kinase family enzyme, TYK2 [1].
Various cytokines and their receptors mediate intracellular signalling through pairs of Janus kinase family enzymes. TYK2 dimerises with JAK2 to mediate IL-12 and IL-23 signalling (both are p40 subunit containing cytokines), and with JAK1 for the IFNα/β pathway. Both of these TYK2-dependent pathways are validated as druggable targets for the development of pharmaceuticals for the treatment of autoimmune diseases. Displacement of the ATP that binds to the JH2 pseudokinase domain allosterically disrupts TYK2 catalytic activity, in a mechanism that appears to stablise the kinase in an auto-inhibitory conformation. Expolting this domain is being investigated with the aim of identifying inhibitors with improved selectivity compared to traditional orthosteric JH1 domain ATP-competitive inhibitors.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 8
Hydrogen bond donors 5
Rotatable bonds 10
Topological polar surface area 133.04
Molecular weight 450.18
XLogP 1.49
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES COc1c(cc(cc1F)F)Nc1cc(NC)c2n(n1)c(cn2)C(=O)NCCC(CO)(O)C
Isomeric SMILES COc1c(cc(cc1F)F)Nc1cc(NC)c2n(n1)c(cn2)C(=O)NCCC(CO)(O)C
InChI InChI=1S/C20H24F2N6O4/c1-20(31,10-29)4-5-24-19(30)15-9-25-18-14(23-2)8-16(27-28(15)18)26-13-7-11(21)6-12(22)17(13)32-3/h6-9,23,29,31H,4-5,10H2,1-3H3,(H,24,30)(H,26,27)
InChI Key BDYFCJQKSYBTAK-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Bioactivity Comments
Compound 29 exhibits >500-fold selectivity for TYK2 JH2 compared to the Janus kinases JH1 domains, and an IC50 of 27 μM vs JAK1 JH2 [1]. PDE4 is a significant off-target of compound 29.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
tyrosine kinase 2 Hs Inhibitor Inhibition 8.4 pIC50 - 1
⤷ pIC50 8.4 (IC50 4x10-9 M) [1]
Description: Measuring binding to the JH2 pseudokinase domain of human TYK2.
phosphodiesterase 4D Hs Inhibitor Inhibition 7.4 pIC50 - 1
⤷ pIC50 7.4 (IC50 4.3x10-8 M) [1]
Description: Binding affinity calculated be measuring displacement of [3H]cAMP binding to purified recombinant His-Tb-hPDE4D2.