新型组蛋白去甲基化酶 LSD1 抑制剂选择性靶向畸胎瘤和胚胎癌细胞。
New histone demethylase LSD1 inhibitor selectively targets teratocarcinoma and embryonic carcinoma cells.
机构信息
Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV, USA.
Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
出版信息
Bioorg Med Chem. 2018 May 1;26(8):1523-1537. doi: 10.1016/j.bmc.2018.01.031. Epub 2018 Feb 7.
LSD1/KDM1 is a histone demethylase that preferentially removes methyl groups from the mono- and di-methylated lysine 4 in histone H3 (H3K4), key marks for active chromatin for transcriptional activation. LSD1 is essential for pluripotent embryonic stem cells and embryonic teratocarcinoma/carcinoma cells and its expression is often elevated in various cancers. We developed a new LSD1 inhibitor, CBB3001, which potently inhibited LSD1 activity both in vitro and in vivo. CBB3001 also selectively inhibited the growth of human ovarian teratocarcinoma PA-1 and mouse embryonic carcinoma F9 cells, caused the downregulation of pluripotent stem cell proteins SOX2 and OCT4. However, CBB3001 does not have significant inhibition on the growth of human colorectal carcinoma HCT116 cells or mouse fibroblast NIH3T3 cells that do not express these stem cell proteins. Our studies strongly indicate that CBB3001 is a specific LSD1 inhibitor that selectively inhibits teratocarcinoma and embryonic carcinoma cells that express SOX2 and OCT4.
LSD1/KDM1 是一种组蛋白去甲基化酶，它优先去除组蛋白 H3（H3K4）上单甲基和二甲基化赖氨酸 4 上的甲基，这是转录激活的活性染色质的关键标记。LSD1 对于多能胚胎干细胞和胚胎畸胎瘤/癌细胞是必不可少的，其表达通常在各种癌症中升高。我们开发了一种新型 LSD1 抑制剂 CBB3001，它在体外和体内均能有效抑制 LSD1 活性。CBB3001 还选择性地抑制人卵巢畸胎瘤 PA-1 和小鼠胚胎癌细胞 F9 的生长，导致多能干细胞蛋白 SOX2 和 OCT4 的下调。然而，CBB3001 对不表达这些干细胞蛋白的人结直肠癌细胞 HCT116 或小鼠成纤维细胞 NIH3T3 细胞的生长没有明显抑制作用。我们的研究强烈表明，CBB3001 是一种特异性 LSD1 抑制剂，可选择性抑制表达 SOX2 和 OCT4 的畸胎瘤和胚胎癌细胞。
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