Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.
Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.
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DOI：
10.1038/s41467-017-02242-4
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发表时间：
2018-01-04
影响因子：
16.6
通讯作者：
Cole PA
中科院分区：
文献类型：
--
作者：
Kalin JH;Wu M;Gomez AV;Song Y;Das J;Hayward D;Adejola N;Wu M;Panova I;Chung HJ;Kim E;Roberts HJ;Roberts JM;Prusevich P;Jeliazkov JR;Roy Burman SS;Fairall L;Milano C;Eroglu A;Proby CM;Dinkova-Kostova AT;Hancock WW;Gray JJ;Bradner JE;Valente S;Mai A;Anders NM;Rudek MA;Hu Y;Ryu B;Schwabe JWR;Mattevi A;Alani RM;Cole PA
在这里，我们报告corin，一种合成的混合剂，来自I类HDAC抑制剂（恩替司他）和LSD 1抑制剂（反苯环丙胺类似物）。酶学分析显示，corin有效地靶向CoREST复合物，并且与恩替司他相比显示出对CoREST复合物HDAC活性的更持续的抑制。基于细胞的实验表明，corin表现出上级抗增殖对几个黑色素瘤细胞系和皮肤鳞状细胞癌细胞系相比，其母体单功能抑制剂，但毒性较低的黑素细胞和角质形成细胞。CoREST敲除、基因表达和ChIP研究表明，科林有利的药理作用可能依赖于完整的CoREST复合物。Corin在黑色素瘤小鼠异种移植模型中也有效减缓肿瘤生长。这些研究突出了一类新的双管齐下的混合剂的前景，可以显示特定的表观遗传调控复合物的优先靶向，并提供独特的治疗机会。表观遗传景观的改变已经涉及几种疾病过程，其中靶向组蛋白修饰剂可能具有治疗应用。在这里，作者报告了一种双功能小分子抑制剂，它同时靶向CoREST复合物的脱乙酰酶（HDAC 1）和脱甲基酶（LSD 1）活性。
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin’s favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities. Alteration of the epigenetic landscape has been implicated in several disease processes, where targeting histone modifiers may have therapeutic applications. Here the authors report a bifunctional small molecule inhibitor that simultaneously targets the deacetylase (HDAC1) and demethylase (LSD1) activities of the CoREST complex.
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影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
DOI：
10.1002/jbt.2570010106
发表时间：
1986-01-01
期刊：
Journal of Biochemical Toxicology
影响因子：
--
作者：
ERIKSON J M;PROUGH R A
通讯作者：
PROUGH R A
影响因子：
56.9
作者：
Bostrom, Jenny;Yu, Shang-Fan;Fuh, Germaine
通讯作者：
Fuh, Germaine
小分子和组蛋白底物类似物作为LSD1赖氨酸脱甲基酶抑制剂的比较分析。
影响因子：
15
作者：
Culhane, Jeffrey C.;Wang, Dongqing;Yen, Paul M.;Cole, Philip A.
通讯作者：
Cole, Philip A.
影响因子：
15
作者：
Binda, Claudia;Valente, Sergio;Mai, Antonello
通讯作者：
Mai, Antonello