Towards the Development of Small-Molecule MO25 Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors
Towards the Development of Small-Molecule MO25 Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors
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开发小分子 MO25 结合剂作为潜在的间接 SPAK/OSR1 激酶抑制剂
DOI：
10.1002/cbic.201600620
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发表时间：
2017
期刊：
影响因子：
3.2
通讯作者：
Kadri H
中科院分区：
文献类型：
--
作者：
Kadri H
支架蛋白MO 25与SPAK和OSR 1蛋白激酶的结合（调节离子稳态）导致其催化活性增加高达100倍。各种动物模型表明，SPAK和OSR 1的抑制可以降低血压，因此在这里，我们提出了一种新的间接方法，通过靶向其蛋白伴侣MO 25来抑制SPAK和OSR 1激酶。为了探索这种方法，我们开发了一种荧光偏振测定法，并将其用于筛选一个小型的内部库，其中包含10000种化合物。这导致鉴定出一种化合物-HK 01-作为SPAK和OSR 1体外MO 25依赖性活化的第一种小分子抑制剂。我们的数据证实了小分子化合物靶向这种蛋白质-蛋白质相互作用的可行性，并强调了它们调节离子共转运蛋白和细胞电解质平衡的潜力。
The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes increases of up to 100‐fold in their catalytic activity. Various animal models have shown that the inhibition of SPAK and OSR1 lowers blood pressure, and so here we present a new indirect approach to inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed a fluorescent polarisation assay and used it in screening of a small in‐house library of ≈4000 compounds. This led to the identification of one compound—HK01—as the first small‐molecule inhibitor of the MO25‐dependent activation of SPAK and OSR1 in vitro. Our data confirm the feasibility of targeting this protein–protein interaction by small‐molecule compounds and highlights their potential to modulate ion co‐transporters and thus cellular electrolyte balance.