Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1.
Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1.
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DOI：
10.1021/jm200502u
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发表时间：
2011-07-28
影响因子：
7.3
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Bachovchin, Daniel A.;Zuhl, Andrea M.;Speers, Anna E.;Wolfe, Monique R.;Weerapana, Eranthie;Brown, Steven J.;Rosen, Hugh;Cravatt, Benjamin F.
丝氨酸水解酶蛋白磷酸酶甲基酯酶-1（PME-1）调节蛋白磷酸酶2A（PP 2A）的甲基化状态，并与癌症和阿尔茨海默病有关。我们最近报道了一种基于荧光偏振活性的蛋白质谱（fluopol-ABPP）高通量筛选PME-1，发现了一类非常有效和选择性的氮杂-β-内酰胺（ABL）PME-1抑制剂。在这里，我们描述了一组不同的磺酰基丙烯腈抑制剂，也出现在这个屏幕上。优化的化合物28（AMZ 30）选择性地灭活PME-1并减少活细胞中PP 2A的去甲基化形式。考虑到28在结构上与PME-1的ABL抑制剂无关，这些药物一起提供了一组有价值的药理学探针来研究甲基化在调节PP 2A功能中的作用。我们还观察到，几个丝氨酸水解酶是敏感的类似物28，这表明更广泛的结构探索的磺酰基丙烯腈化学型可能会导致有用的抑制剂为其他成员的这个大的酶类。
The serine hydrolase protein phosphatase methylesterase-1 (PME-1) regulates the methylesterification state of protein phosphatase 2A (PP2A) and has been implicated in cancer and Alzheimer's disease. We recently reported a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) high-throughput screen for PME-1 that uncovered a remarkably potent and selective class of aza-β-lactam (ABL) PME-1 inhibitors. Here, we describe a distinct set of sulfonyl acrylonitrile inhibitors that also emerged from this screen. The optimized compound, 28 (AMZ30), selectively inactivates PME-1 and reduces the demethylated form of PP2A in living cells. Considering that 28 is structurally unrelated to ABL inhibitors of PME-1, these agents, together, provide a valuable set of pharmacological probes to study the role of methylation in regulating PP2A function. We furthermore observed that several serine hydrolases were sensitive to analogs of 28, suggesting that more extensive structural exploration of the sulfonyl acrylonitrile chemotype may result in useful inhibitors for other members of this large enzyme class.
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影响因子：
14.8
作者：
Adibekian, Alexander;Martin, Brent R.;Wang, Chu;Hsu, Ku-Lung;Bachovchin, Daniel A.;Niessen, Sherry;Hoover, Heather;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
4.1
作者：
Bryant, JC;Westphal, RS;Wadzinski, BE
通讯作者：
Wadzinski, BE
影响因子：
2.7
作者：
Hoover, Heather S.;Blankman, Jacqueline L.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
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作者：
Blankman, Jacqueline L.;Simon, Gabriel M.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
46.9
作者：
Leung, D;Hardouin, C;Cravatt, BF
通讯作者：
Cravatt, BF