靶向蛋白丝氨酸/苏氨酸磷酸酶用于药物研发。
Targeting protein serine/threonine phosphatases for drug development.
作者信息
McConnell Jamie L, Wadzinski Brian E
机构信息
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6600, USA.
出版信息
Mol Pharmacol. 2009 Jun;75(6):1249-61. doi: 10.1124/mol.108.053140. Epub 2009 Mar 19.
Abstract
With the recent clinical success of drugs targeting protein kinase activity, drug discovery efforts are focusing on the role of reversible protein phosphorylation in disease states. The activity of protein phosphatases, enzymes that oppose protein kinases, can also be manipulated to alter cellular signaling for therapeutic benefits. In this review, we present protein serine/threonine phosphatases as viable therapeutic targets, discussing past successes, current challenges, and future strategies for modulating phosphatase activity.
摘要
随着近期靶向蛋白激酶活性药物在临床上取得成功，药物研发工作正聚焦于可逆性蛋白磷酸化在疾病状态中的作用。蛋白磷酸酶是与蛋白激酶作用相反的酶，其活性也可被调控，以改变细胞信号传导从而获得治疗益处。在本综述中，我们将蛋白丝氨酸/苏氨酸磷酸酶作为可行的治疗靶点进行阐述，讨论过去的成功案例、当前面临的挑战以及调节磷酸酶活性的未来策略。
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本文引用的文献
1
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FASEB J. 2009 Mar;23(3):751-63. doi: 10.1096/fj.08-120550. Epub 2008 Nov 21.
2
Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition.去甲斑蝥素类似物：合成、抗癌活性及对蛋白磷酸酶1和2A的抑制作用
ChemMedChem. 2008 Dec;3(12):1878-92. doi: 10.1002/cmdc.200800192.
3
ICP34.5-dependent and -independent activities of salubrinal in herpes simplex virus-1 infected cells.在单纯疱疹病毒1感染细胞中，Salubrinal依赖和不依赖于ICP34.5的活性。
Virology. 2008 Sep 30;379(2):197-204. doi: 10.1016/j.virol.2008.06.028. Epub 2008 Aug 6.
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5
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