化学
立体化学
活动站点
蛋白质亚单位
蛋白酶体
酰胺
结合位点
酶
结构-活动关系
生物化学
组合化学
体外
基因
作者
Roberta Ettari,Nunzio Iraci,Carla Di Chio,Santo Previti,Mariafernanda Danzè,Maria Zappalà
标识
DOI:10.1016/j.bmcl.2021.128478
摘要
The inhibition of immunoproteasome is considered nowadays a promising strategy for the treatment of hematologic malignancies. In this paper we report the design, synthesis, and biological evaluation as immunoproteasome inhibitors of a new series of isoquinolinone derivatives characterized by a (E)-prop-1-ene fragment that connects the heterocycle to a distal amide functionality. Among all the synthesized compounds, we identified an inhibitor with Ki values in the low micromolar or submicromolar range towards the chymotrypsin-like activities of both proteasome and immunoproteasome (β5c, β5i and β1i subunits). Molecular modeling studies suggest that the most potent compound of the series may act a single-site binder. In particular, through its isopentyl group, it might dock into P1 site in the case of the β1i catalytic subunit, while in the case of β5c and β5i subunits, the P3 site might be the preferred binding site.
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