Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.

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.

在此我们报道了一种名为corin的合成杂合药物，它源自I类组蛋白去乙酰化酶（HDAC）抑制剂（恩替诺特）和一种赖氨酸特异性去甲基化酶1（LSD1）抑制剂（反苯环丙胺类似物）。酶学分析显示，corin能有效作用于CoREST复合物，并且相较于恩替诺特，对CoREST复合物的HDAC活性具有更持久的抑制作用。基于细胞的实验表明，与它的母体单功能抑制剂相比，corin对几种黑色素瘤细胞系和皮肤鳞状细胞癌细胞系表现出更优的抗增殖特性，但对黑素细胞和角质形成细胞的毒性更小。CoREST基因敲低、基因表达以及染色质免疫沉淀（ChIP）研究表明，corin良好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能有效减缓肿瘤生长。这些研究凸显了一类新型双管齐下的杂合药物的前景，这类药物可能对特定的表观遗传调控复合物具有选择性靶向作用，并提供独特的治疗机会。 表观遗传景观的改变与多种疾病进程有关，针对组蛋白修饰因子可能具有治疗应用。在此作者报道了一种双功能小分子抑制剂，它可同时作用于CoREST复合物的去乙酰化酶（HDAC1）和去甲基化酶（LSD1）活性。