小分子以非竞争性方式与核因子 κB 激酶亚基 β抑制剂结合。
Small molecule binding to inhibitor of nuclear factor kappa-B kinase subunit beta in an ATP non-competitive manner.
机构信息
Eppley Institute for Research in Cancer and Allied Diseases, UNMC, USA.
Mass Spectrometry and Proteomics Core Facility, UNMC, USA.
出版信息
Chem Commun (Camb). 2021 May 11;57(38):4678-4681. doi: 10.1039/d1cc01245b.
Abstract
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is a key regulator of the cannonical NF-κB pathway. IKKβ has been validated as a drug target for pathological conditions, which include chronic inflammatory diseases and cancer. Pharmacological studies revealed that chronic administration of ATP-competitive IKKβ inhibitors resulted in unexpected toxicity. We previously reported the discovery of 13-197 as a non-toxic IKKβ inhibitor that reduced tumor growth. Here, we show that 13-197 inhibits IKKβ in a ATP non-competitive manner and an allosteric pocket at the interface of the kinase and ubiquitin like domains was identified as the potential binding site.
摘要
核因子 kappa-B 激酶亚基β（IKKβ）抑制剂是经典 NF-κB 通路的关键调节剂。IKKβ 已被验证为病理状况的药物靶点，包括慢性炎症性疾病和癌症。药理学研究表明，ATP 竞争性 IKKβ 抑制剂的慢性给药会导致意外的毒性。我们之前报道了发现 13-197 作为一种非毒性的 IKKβ 抑制剂，可降低肿瘤生长。在这里，我们表明 13-197 以非 ATP 竞争性方式抑制 IKKβ，并且在激酶和泛素样结构域的界面处鉴定出别构口袋作为潜在的结合位点。
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