Abstract

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-κB 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 IC₅₀ of 27 nM. It showed a reversible reaction with β-mercaptoethanol, which supports its potential as a reversible covalent inhibitor.

摘要

许多研究证明了转化生长因子 β 活化激酶 1 (TAK1) 对细胞存活的重要性。TAK1 调节信号级联、NF-κB 通路和丝裂原活化蛋白激酶 (MAPK) 通路。TAK1抑制剂可诱导癌细胞凋亡，(5Z)-7-oxozaeenol等不可逆抑制剂具有高效力。然而，它们可以与蛋白质中的半胱氨酸残基发生非特异性反应，这可能会产生严重的副作用。已建议使用可逆共价抑制剂作为替代品。我们合成了咪唑并吡啶衍生物作为新型 TAK1 抑制剂，其具有可形成可逆共价键的 2-氰基丙烯酰胺部分。2-氰基-3-(6-甲基吡啶-2-基)丙烯酰胺的衍生物（13h) 表现出有效的 TAK1 抑制活性，IC ₅₀为 27 nM。它显示出与 β-巯基乙醇的可逆反应，这支持了它作为可逆共价抑制剂的潜力。