Histone Lysine deMethylation: Structures, Inhibitions and Mechanisms

 描述(由申请人提供)：表观遗传调控构成了一套极其重要的基因控制机制，它深刻地影响着染色质的功能，与许多人类疾病直接相关。组蛋白赖氨酸甲基化和去甲基化是组蛋白密码的组成部分，这些甲基标记的识别是表观遗传调控的基础。例如，已注意到组蛋白赖氨酸去甲基酶PHF8在前列腺癌样本中的过度表达，它与侵袭性增加和预后较差有关。表观遗传修饰的内在可逆性使修饰组蛋白和DNA的酶成为治疗干预的候选对象。到目前为止，这种表观遗传疗法主要集中在调节组蛋白乙酰化和DNA甲基化的酶上，几种HDAC和DNMT抑制剂现在临床上使用，FDA批准用于治疗白血病和其他癌症。随着新的组蛋白甲基转移酶抑制剂最近进入临床前试验，参与调节组蛋白甲基化模式和水平的酶已成为非常有希望的治疗靶点。另一方面，组蛋白赖氨酸去甲基酶(属于非血红素Fe(II)依赖的双加氧酶)仍然是一个相对未被开发的潜在“可用药靶点”的来源。这项建议的中心目标是在体外验证、重新设计和合成组蛋白赖氨酸去甲基酶的小分子抑制剂，并研究天然(ISO)黄酮衍生物抑制作用的机制(S)。

 DESCRIPTION (provided by applicant): Epigenetic regulation constitutes a fundamentally important set of gene control mechanisms that profoundly influence chromatin function, with direct relevance to a large number of human diseases. Histone lysine methylation and demethylation are components of a "histone code", and the recognition of these methyl marks underlies epigenetic regulation. For example, overexpression of a histone lysine demethylase, PHF8, has been noted in primary prostate cancer samples, where it is associated with increased invasiveness and a poorer prognosis. The inherently reversible nature of epigenetic modifications makes enzymes that modify histones and DNA attractive candidates for therapeutic intervention. Thus far such epigenetic therapies have focused on the enzymes that regulate histone acetylation and DNA methylation, with several HDAC and DNMT inhibitors now in clinical use and FDA approved for the treatment of leukemias and other cancers. The enzymes involved in regulating histone methylation patterns and levels have emerged as highly promising therapeutic targets, with newer histone methyltransferase inhibitors recently entering preclinical testing. Histone lysine demethylases (belong to a broad family of non-heme Fe(II)-dependent dioxygenases), on the other hand, remain a relatively untapped source of potential "druggable targets". The central goal of this proposal is to validate, re-design, and synthesize small molecule inhibitors of histone lysine demethylases in vitro, and to investigate the mechanism(s) of inhibition by nature (iso)flavone derivatives.