鉴定新型 SGK1 抑制剂结构家族,作为潜在的神经保护剂。

Identification of a new structural family of SGK1 inhibitors as potential neuroprotective agents.

机构信息

Centro de Investigaciones, Biológicas Margarita Salas-CSIC, Madrid, Spain.

Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.

出版信息

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2153841. doi: 10.1080/14756366.2022.2153841.

Abstract

SGK1 is a serine/threonine kinase involved in several neurodegenerative-related pathways such as apoptosis, neuroinflammation, ionic channel regulation, and autophagy, among others. Despite its potential role as a pharmacological target against this kind of diseases, there are no reported inhibitors able to cross the BBB so far, being a field yet to be explored. In this context, a structure-based virtual screening against this kinase was performed, pointing out the deazapurine moiety as an interesting and easy-to-derivatize scaffold. Moreover, these inhibitors are able to i) exert neuroprotection in an model of AD and ii) block mitophagy in a PRKN-independent manner, reinforcing the hypothesis of SGK1 inhibitors as neuroprotective chemical tools.

摘要

SGK1 是一种丝氨酸/苏氨酸激酶,参与多种与神经退行性相关的途径,如细胞凋亡、神经炎症、离子通道调节和自噬等。尽管它作为一种针对这类疾病的药理学靶点具有潜在的作用,但到目前为止,还没有报道能够穿过血脑屏障的抑制剂,这是一个有待探索的领域。在这种情况下,针对这种激酶进行了基于结构的虚拟筛选,指出去氮嘌呤部分是一种有趣且易于衍生的支架。此外,这些抑制剂能够:i)在 AD 模型中发挥神经保护作用;ii)以不依赖 PRKN 的方式阻断线粒体自噬,这进一步支持了 SGK1 抑制剂作为神经保护化学工具的假说。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf40/9848319/2aecd6a9a7ca/IENZ_A_2153841_F0001_C.jpg

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