The p38alpha mitogen-activated protein kinase as a central nervous system drug discovery target.
The p38alpha mitogen-activated protein kinase as a central nervous system drug discovery target.
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DOI：
10.1186/1471-2202-9-s2-s12
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发表时间：
2008-12-03
期刊：
影响因子：
2.4
通讯作者：
Watterson DM
中科院分区：
文献类型：
--
作者：
Borders AS;de Almeida L;Van Eldik LJ;Watterson DM
蛋白激酶是多种细胞信号转导途径的关键调节剂，并且异常磷酸化事件可以是多种病症中疾病进展的原因或促成因素。这导致了蛋白激酶作为小分子治疗的一类重要的新药物靶标的出现。一种丝氨酸/苏氨酸蛋白激酶，p38α丝裂原活化蛋白激酶（MAPK），由于其在调节促炎细胞因子产生中的关键作用，是外周炎性疾病的既定治疗靶点。越来越多的证据表明，p38α MAPK也是中枢神经系统中促炎细胞因子水平的重要调节因子，这增加了激酶可能成为中枢神经系统疾病药物发现靶点的可能性，其中细胞因子过度产生导致疾病进展。生物可利用的、中枢神经系统渗透性p38α MAPK抑制剂的开发为针对神经退行性疾病中p38α MAPK的药物发现活动提供了所需的基础。
Protein kinases are critical modulators of a variety of cellular signal transduction pathways, and abnormal phosphorylation events can be a cause or contributor to disease progression in a variety of disorders. This has led to the emergence of protein kinases as an important new class of drug targets for small molecule therapeutics. A serine/threonine protein kinase, p38α mitogen-activated protein kinase (MAPK), is an established therapeutic target for peripheral inflammatory disorders because of its critical role in regulation of proinflammatory cytokine production. There is increasing evidence that p38α MAPK is also an important regulator of proinflammatory cytokine levels in the central nervous system, raising the possibility that the kinase may be a drug discovery target for central nervous system disorders where cytokine overproduction contributes to disease progression. Development of bioavailable, central nervous system-penetrant p38α MAPK inhibitors provides the required foundation for drug discovery campaigns targeting p38α MAPK in neurodegenerative disorders.