2-Sulfonylpyrimidines Target the Kinesin HSET via Cysteine Alkylation
2-Sulfonylpyrimidines Target the Kinesin HSET via Cysteine Alkylation
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DOI：
10.1002/ejoc.201900586
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发表时间：
2019-09-01
影响因子：
2.8
通讯作者：
Waldmann, Herbert
中科院分区：
文献类型：
--
作者：
Foerster, Tim;Shang, Erchang;Waldmann, Herbert
多余中心体是非整倍体的来源，细胞采用不同的机制来避免多极有丝分裂。在中心体扩增的癌细胞中，驱动蛋白HSET是伪双极有丝分裂所必需的，抑制HSET活性被认为是一种潜在的抗癌方法。我们报告鉴定2-磺酰基嘧啶抑制剂的HSET酶活性。HSET抑制导致多极有丝分裂的建立，同时抑制运动蛋白Eg5恢复双极纺锤体的形成。结构与活性的相关性表明，该类化合物的活性需要2-磺酰基嘧啶基，并且2-磺酰基嘧啶共价修饰HSET。此外，这些亲电试剂与谷胱甘肽反应，从而引起氧化应激。如果2-磺酰基嘧啶将用于开发具有生物活性的小分子，则需要考虑到这种一般反应性。
Supernumerary centrosomes are a source of aneuploidy, and cells have adopted different mechanisms to avoid multipolar mitoses. The kinesin HSET is required for pseudo-bipolar mitoses in cancer cells with amplified centrosomes and suppression of HSET activity is regarded a potential anti-cancer approach. We report the identification of 2-sulfonylpyrimidine inhibitors of HSET enzymatic activity. HSET inhibition results in establishment of multipolar mitoses and simultaneous inhibition of the kinesin Eg5 restored bipolar spindle formation. Correlation of structure to activity revealed that the 2-sulfonylpyrimidinyl group is required for the activity of the compound class and that 2-sulfonylpyrimidines covalently modify HSET. In addition, these electrophiles react with glutathione, thereby causing oxidative stress. This general reactivity needs to be taken into account if 2-sulfonylpyrimidines will be employed in the development of biologically active small molecules.