JAK3 inhibitor 32   Click here for help

GtoPdb Ligand ID: 10156

Synonyms: compound 32 [PMID: 30423248]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Compound 32 is an exemplar selective and covalent Janus kinase 3 (JAK3) inhibitor that was discovered by Casimiro-Garcia et al. [1]. It was designed such that its cyanamide group directly engages the Cys909 residue in JAK3, and it exhibits irreversible binding in a competition binding assay.
Click here for help

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.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

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.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. 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.

✖
Hydrogen bond acceptors 7
Hydrogen bond donors 3
Rotatable bonds 5
Topological polar surface area 131.94
Molecular weight 448.11
XLogP 3.3
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Click here for help

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.

✖
Canonical SMILES N#CNC1CC(c2c1cc(cc2)c1ncnc2c1cc[nH]2)NS(=O)(=O)c1cccc(c1)F
Isomeric SMILES N#CN[C@H]1C[C@H](c2c1cc(cc2)c1ncnc2c1cc[nH]2)NS(=O)(=O)c1cccc(c1)F
InChI InChI=1S/C22H17FN6O2S/c23-14-2-1-3-15(9-14)32(30,31)29-20-10-19(26-11-24)18-8-13(4-5-16(18)20)21-17-6-7-25-22(17)28-12-27-21/h1-9,12,19-20,26,29H,10H2,(H,25,27,28)/t19-,20+/m0/s1
InChI Key MLJSOTTYIVCEQO-VQTJNVASSA-N
Bioactivity Comments
Inhibitor 32 exhibits 246-fold selectivity for JAK3 compared to the other JAK subfamily members, and does not substantially inhibit other kinases that have a Cys residue in a position analogous to Cys909 in JAK3 (the only within-range IC50 being 3390 nM for BMX) [1]. Mechanistically compound 32 mediates a reduction in IL-15 induced STAT5 phosphorylation via the JAK1/JAK3 heterodimer (IC50 331 nM in PBMCs), but has no effect on IL-10 mediated STAT3 phosphorylation via the JAK1/TYK2 heterodimer, which confirms the JAK3 specificity of the compound.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Janus kinase 3 Primary target of this compound Hs Inhibitor Inhibition 8.0 pIC50 - 1
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [1]
Janus kinase 1 Hs Inhibitor Inhibition 5.6 pIC50 - 1
⤷ pIC50 5.6 (IC50 2.703x10-6 M) [1]
Janus kinase 2 Hs Inhibitor Inhibition 5.5 pIC50 - 1
⤷ pIC50 5.5 (IC50 3.012x10-6 M) [1]
tyrosine kinase 2 Hs Inhibitor Inhibition <5.0 pIC50 - 1
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [1]