From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure-Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II)
From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure-Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II)
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DOI：
10.1021/acs.jmedchem.5b01439
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发表时间：
2016-02-11
影响因子：
7.3
通讯作者：
Flynn, Bernard L.
中科院分区：
文献类型：
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作者：
Aurelio, Luigi;Scullino, Carmen V.;Flynn, Bernard L.
鞘氨醇激酶（SK）抑制剂，SKI-II，已被广泛用于生物学研究的SK 1和SK 2在疾病中的作用，并已在体外和体内表现出令人印象深刻的抗癌活性。然而，使用这种药物的结果的解释是复杂的几个因素：SK 1/2选择性差，额外的活性作为诱导剂的SK 1降解，脱靶效应，包括其最近确定的能力，抑制二氢神经酰胺去饱和酶-1（Des 1）。在这项研究中，我们描绘了这些不同的目标的结构-活性关系（SAR），并将它们与抗癌活性所需的相关性，并确定Des 1抑制主要是负责SKI-II及其类似物的抗增殖作用。在这些努力的过程中，已经产生了一系列新的SK 1、SK 2和Des 1抑制剂，包括具有显著更高抗癌活性的化合物。
The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results using this pharmacological agent are complicated by several factors: poor SK1/2 selectivity, additional activity as an inducer of SK1-degradation, and off-target effects, including its recently identified capacity to inhibit dihydroceramide desaturase-1 (Des1). In this study, we have delineated the structure-activity relationship (SAR) for these different targets and correlated them to that required for anticancer activity and determined that Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. In the course of these efforts, a series of novel SK1, SK2, and Des1 inhibitors have been generated, including compounds with significantly greater anticancer activity.