Yang Chao, Wang Wanhe, Liang Jia-Xin, Li Guodong, Vellaisamy Kasipandi, Wong Chun-Yuen, Ma Dik-Lung, Leung Chung-Hang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau, China.
Department of Chemistry, Hong Kong Baptist University , Kowloon Tong, Hong Kong, China.
J Med Chem. 2017 Mar 23;60(6):2597-2603. doi: 10.1021/acs.jmedchem.7b00133. Epub 2017 Mar 1.
We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells and enhanced the amplification of p21, FOXA2, and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7, and MAO activities, and also showed antiproliferative activity toward human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.
我们在此报告一种新型铑（III）配合物1，它是一种新的靶向赖氨酸特异性去甲基化酶1（LSD1）的试剂和表观遗传调节剂。配合物1破坏了人前列腺癌细胞中LSD1与组蛋白H3第4位赖氨酸二甲基化（H3K4me2）的相互作用，并增强了p21、叉头框蛋白A2（FOXA2）和骨形态发生蛋白2（BMP2）基因启动子的扩增。配合物1对LSD1具有选择性，优于其他组蛋白去甲基化酶，如赖氨酸特异性去甲基化酶2B（KDM2b）、赖氨酸特异性去甲基化酶7（KDM7）和单胺氧化酶（MAO）的活性，并且对人癌细胞也显示出抗增殖活性。迄今为止，配合物1是第一种基于金属的LSD1活性抑制剂。
