The University of Manchester, Paterson Institute for Cancer Research, Cancer Research UK Leukaemia Biology Laboratory, Manchester, M20 4BX, UK.
Expert Opin Ther Targets. 2012 Dec;16(12):1239-49. doi: 10.1517/14728222.2012.722206. Epub 2012 Sep 8.
The role of epigenetic dysfunction in cancer is increasingly appreciated. This has raised the question as to whether enzymes that regulate the structure and function of chromatin might represent novel therapeutic targets. The histone demethylase LSD1 is one such candidate and novel, potent inhibitors are under development.
The literature on LSD1 (also known as KDM1A, AOF2, BHC110 or KIAA0601) was identified in Pubmed and is herein discussed. Areas covered include the structure and enzymatic activity of LSD1, its role in chromatin regulatory complexes, its functional roles in normal and malignant tissue, pharmacological inhibitors of its activity and their putative therapeutic roles.
Pre-clinical data supporting a therapeutic role for LSD1 inhibitors are most encouraging in acute myeloid leukaemia, although optimal dosing strategies and beneficial combinations with other agents remain unclear. Studies making use of potent, selective LSD1 inhibitors active in the nanomolar range are required to establish therapeutic indications in other subtypes of haematological malignancy, and in solid tumours.
表观遗传功能障碍在癌症中的作用正日益受到重视。这就提出了一个问题，即调节染色质结构和功能的酶是否可能代表新的治疗靶点。组蛋白去甲基化酶 LSD1 就是这样的候选者之一，新型强效抑制剂正在开发中。
在 Pubmed 上确定了 LSD1（也称为 KDM1A、AOF2、BHC110 或 KIAA0601）的相关文献，并在此进行讨论。涵盖的领域包括 LSD1 的结构和酶活性、其在染色质调节复合物中的作用、在正常和恶性组织中的功能作用、其活性的药理学抑制剂及其潜在的治疗作用。
支持 LSD1 抑制剂具有治疗作用的临床前数据在急性髓系白血病中最为令人鼓舞，尽管最佳剂量策略和与其他药物的有益组合仍不清楚。需要使用在纳摩尔范围内具有活性的强效、选择性 LSD1 抑制剂来确定在其他血液恶性肿瘤和实体肿瘤亚型中的治疗适应症。
