Abstract：
:Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Forster M,Chaikuad A,Bauer SM,Holstein J,Robers MB,Corona CR,Gehringer M,Pfaffenrot E,Ghoreschi K,Knapp S,Laufer SAdoi
10.1016/j.chembiol.2016.10.008subject
Has Abstractpub_date
2016-11-17 00:00:00pages
1335-1340issue
11eissn
2451-9456issn
2451-9448pii
S2451-9456(16)30386-5journal_volume
23pub_type
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