摘要
组蛋白乙酰转移酶(HAT)是表观驱动因子,其催化从乙酰辅酶A向组蛋白和非组蛋白底物的赖氨酸的乙酰基转移,从而通过染色质重塑或直接转录因子活化来诱导转录。组蛋白去乙酰化酶(HDAC)进行逆向反应来抵消HAT活性。诸如细胞周期进程或细胞凋亡的生理过程需要乙酰化和脱乙酰化过程之间相互作用的完全平衡的平衡,以维持或如果需要的话改变整体乙酰化状态。最近已经证实异常HAT活性在各种疾病如前列腺癌,肺癌和结肠癌以及成胶质细胞瘤和神经退行性疾病的进展中起关键作用。最近的研究旨在鉴定HAT调节剂以进一步破译乙酰转移酶相关信号级联的复杂性,并发现药物设计方法的潜在领导。 HDAC已经被小分子广泛地表征和靶向,包括四种FDA批准的HDAC抑制剂;相比之下,HAT尚未成为治疗发展的积极目标。本综述将总结HAT相关疾病的状况以及目前已知和可用的HAT抑制剂的发现,进一步改进和当前应用的情况。
关键词: 组蛋白乙酰转移酶,p300 / CBP,PCAF,GCN5,Tip60,表观遗传学,小分子抑制剂,癌症。
图形摘要
Current Medicinal Chemistry
Title:Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease
Volume: 24 Issue: 37
关键词: 组蛋白乙酰转移酶,p300 / CBP,PCAF,GCN5,Tip60,表观遗传学,小分子抑制剂,癌症。
摘要: Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the acetyl transfer from acetyl-CoA to lysines of both histone and non-histone substrates and thereby induce transcription either by chromatin remodeling or direct transcription factor activation. Histone deacetylases (HDACs) conduct the reverse reaction to counter HAT activity. Physiological processes such as cell cycle progression or apoptosis require a thoroughly balanced equilibrium of the interplay between acetylation and deacetylation processes to maintain or, if required, alter the global acetylome status. Aberrant HAT activity has recently been demonstrated to play a crucial role in the progression of various diseases such as prostate, lung, and colon cancers as well as glioblastomas and neurodegenerative diseases. Recent investigations have aimed for the identification of HAT modulators to further decipher the complexity of acetyl transferase related signaling cascades and discover potential leads for drug design approaches. HDACs have been extensively characterized and targeted by small molecules, including four FDA-approved HDAC inhibitors; in contrast, HATs have not been active targets for therapeutic development. This review will summarize the status of HAT associated diseases and the arsenal of currently known and available HAT inhibitors with respect to their discovery, further improvements, and current applications.
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Cite this article as:
Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease, Current Medicinal Chemistry 2017; 24 (37) . https://dx.doi.org/10.2174/0929867324666170223153115
DOI https://dx.doi.org/10.2174/0929867324666170223153115 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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