化学
组蛋白脱乙酰基酶
胶质瘤
HDAC6型
乙酰化
单胺氧化酶
单胺氧化酶B
药理学
单胺类神经递质
IC50型
癌症研究
异羟肟酸
组蛋白脱乙酰酶抑制剂
体内
组蛋白
生物化学
酶
体外
生物
立体化学
受体
血清素
基因
生物技术
作者
Samir Mehndiratta,Bin Qian,Jian Ying Chuang,Jing‐Ping Liou,Jean C. Shih
标识
DOI:10.1021/acs.jmedchem.1c01726
摘要
Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 μM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.
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