Janus kinases (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. There are three known proteins in this family that share a similar protein domain structure: a kinase domain, a regulatory 'pseudo'-kinase domain, an SH2 domain and a FERM domain. Inhibitors of JAK kinases have their therapeutic application in the treatment of cancer and inflammatory diseases.
To design a Janus Kinases Targeted Library a reference set of known JAK1, JAK2 and JAK3 inhibitors from the ChEMBL database has been used. Key amino acid residues involved in inhibitor binding were identified by docking with Surflex-Dock tool. On the basis of the protein-ligand interaction data, three different binding models were prepared with SYBYL-X Unity Module (screening tool).
The entire Life Chemicals Stock Compound Collection was processed with filters for detection and removal of Pan Assay Interference (PAINS) compounds. Docking of the compounds set passed through these filters resulted in about 600 molecules combined in 3 libraries focused against three JAK kinases (Fig.1), with some overlapping between these libraries:
- JAK1 – 83 compounds
- JAK2 – 338 compounds
- JAK3 – 262 compounds
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Fig.1. A. Docking of the compound F0580-0043 in the ATP-binding site of JAK2 kinase. B. Docking of the compound F0373-1247 in the ATP-binding site of JAK3.