Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 35, Issue 1, Pages 1928-1936Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2020.1833876
Keywords
TAK1; imidazopyridine; 2-cyanoacrylamide; reversible covalent chemistry; small molecule inhibitor
Funding
- Advanced Research Center Program of the Korean Government [2015R1A5 A1008958]
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The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-kappa B pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2-cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC(50)of 27 nM. It showed a reversible reaction with beta-mercaptoethanol, which supports its potential as a reversible covalent inhibitor.
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