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.
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2D Structure
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Physico-chemical Properties
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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
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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
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
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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]