Design, Synthesis, and Structure-Activity Relationship of Novel LSD1 Inhibitors Based on Pyrimidine-Thiourea Hybrids As Potent, Orally Active Antitumor Agents
Design, Synthesis, and Structure-Activity Relationship of Novel LSD1 Inhibitors Based on Pyrimidine-Thiourea Hybrids As Potent, Orally Active Antitumor Agents
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基于嘧啶-硫脲杂化物的新型 LSD1 抑制剂的设计、合成和构效关系作为有效的口服活性抗肿瘤药物
DOI：
10.1021/acs.jmedchem.5b00037
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发表时间：
2015-02-26
影响因子：
7.3
通讯作者：
Liu, Hong-Min
中科院分区：
文献类型：
--
作者：
Ma, Li-Ying;Zheng, Yi-Chao;Liu, Hong-Min
组蛋白赖氨酸特异性去甲基酶1(LSD1)在多种人类肿瘤中高表达，被认为是一种很有前途的抗癌药物靶点。在本研究中，我们设计并合成了一系列新型的嘧啶-硫脲杂化化合物，并对其潜在的LSD1抑制作用进行了评价。其中一个化合物6b含有末端的炔基团，在体外是最有效和选择性最强的LSD1抑制剂，对过表达LSD1的胃癌细胞有很强的细胞毒作用。化合物6b对细胞的迁移和侵袭也有明显的抑制作用，在体内具有显著的抑瘤和抗转移作用，口服给药无明显副作用。我们的发现表明，基于嘧啶-硫脲的LSD1失活剂可能是针对LSD1过表达癌症的主要化合物。
Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and synthesized a novel series of pyrimidine-thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine-thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.