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组非常重要的基因控制机制，深刻影响染色质功能，与大量人类疾病直接相关。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，在原发性前列腺癌样本中已经注意到组蛋白赖氨酸脱甲基酶PHF 8的过表达，其中它与增加的侵袭性和较差的预后相关。表观遗传修饰的固有可逆性质使得修饰组蛋白和DNA的酶成为治疗干预的有吸引力的候选者。到目前为止，这种表观遗传疗法集中在调节组蛋白乙酰化和DNA甲基化的酶上，目前有几种HDAC和DNMT抑制剂在临床上使用，FDA批准用于治疗白血病和其他癌症。参与调节组蛋白甲基化模式和水平的酶已经成为非常有前途的治疗靶点，最近新的组蛋白甲基转移酶抑制剂进入临床前测试。另一方面，组蛋白赖氨酸脱甲基酶（属于非血红素Fe（II）依赖性双加氧酶的广泛家族）仍然是潜在的"可药用靶标"的相对未开发的来源。本研究的主要目的是在体外验证、重新设计和合成组蛋白赖氨酸脱甲基酶的小分子抑制剂，并研究天然（异）黄酮衍生物的抑制机制。

 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.