Epigenetics


Epigenetics research delves into the molecular mechanisms that control gene expression and cellular traits without altering the underlying DNA sequence. One crucial aspect of this field is the role of small molecules, which act as powerful regulators of epigenetic modifications. These small compounds, typically comprising a few dozen to a few hundred atoms, have emerged as essential tools in understanding and manipulating the epigenome.
- DNA Methylation Inhibitors: Small molecules like 5-azacytidine and 5-aza-2'-deoxycytidine are DNA methyltransferase inhibitors. They block the addition of methyl groups to DNA, leading to DNA demethylation. This can reactivate silenced genes, potentially offering therapeutic avenues for conditions like cancer.
- HDAC inhibitors: HDACs remove acetyl groups from histone proteins, contributing to gene repression. Small molecule HDAC inhibitors, such as Vorinostat and Romidepsin, can reverse this process by increasing histone acetylation, allowing genes to be more accessible for transcription. These inhibitors are being explored for cancer therapy and other conditions.
- Histone Methyltransferase Inhibitors: Small molecules like GSK126 inhibit specific histone methyltransferases, affecting histone methylation patterns. This can alter gene expression, making them promising candidates for cancer and other diseases with epigenetic dysregulation.
- RNA Modulators: Small molecules can also target non-coding RNAs involved in epigenetic regulation. For instance, small molecules called small interfering RNAs (siRNAs) can be designed to target and degrade specific long non-coding RNAs, influencing gene expression.
- Epigenetic Reader Domain Inhibitors: These small molecules target proteins that recognize and bind to specific epigenetic marks. Examples include inhibitors of bromodomain-containing proteins (BET inhibitors), which can disrupt gene regulation by interfering with protein-DNA interactions.
Small molecules in epigenetics research not only provide insights into the fundamental biology of gene regulation but also hold immense promise for developing novel therapeutics. Their ability to selectively modulate specific epigenetic marks and pathways has led to ongoing clinical trials and drug development efforts for various diseases, including cancer, neurological disorders, and inflammatory conditions. Understanding and harnessing the power of these small molecules is at the forefront of modern epigenetics research, offering new hope for precision medicine and targeted therapies.
3 key components involved in the regulation of epigenetic modifications
Epigenetics Writer
Epigenetics writers are enzymes responsible for adding chemical marks or modifications to DNA or histone proteins. These marks include DNA methylation (addition of methyl groups to DNA) and histone modifications (such as acetylation, methylation, phosphorylation, etc.).
Epigenetics Reader
Function: Epigenetics readers are proteins that can recognize and bind to specific epigenetic marks on DNA or histones. These reader proteins interpret the epigenetic code and facilitate downstream cellular processes, such as gene activation or repression.
Epigenetics Eraser
Function: Epigenetics erasers are enzymes responsible for removing or reversing epigenetic marks on DNA or histones. This process allows for the dynamic regulation of gene expression and the resetting of epigenetic states during various stages of development and in response to environmental changes.
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BRD4-BD1 抑制剂
BRD4 Inhibitor-10 是一种强效的 BRD4-BD1 抑制剂,源自专利 WO2015022332A1,化合物 II-25,具有 8 nM 的 IC50。 -
TYK2 抑制剂
BMS-986165 是一种高效且选择性的 TYK2 配体抑制剂。BMS-986165 阻断 Il-12、IL-23 和 type I Interferon 信号传导,并在炎症性肠病的临床前模型中显示出强大的疗效。 -
Bromodomain 抑制剂
Bromodomain IN-1 是一种从专利 WO2016069578A1 提取的 Bromodomain 抑制剂,化合物编号为 4。 -
HDAC 抑制剂
CHDI-390576 是一种强效的、能渗透细胞并能穿透中枢神经系统(CNS)的 IIa 类组蛋白去乙酰化酶(HDAC)抑制剂,对 IIa 类 HDAC4、HDAC5、HDAC7、HDAC9 的半抑制浓度(IC50)分别为 54 nM、60 nM、31 nM、50 nM,显示出对 I 类 HDACs(1, 2, 3)的选择性高于500倍,以及对 HDAC8 和 IIb 类 HDAC6 亚型的选择性约150倍。 -
JAK3 covalent 抑制剂
JAK3 covalent inhibitor-1 是一种强效且选择性的 janus kinase 3 (JAK3) 共价抑制剂,其 IC50 为 11 nM,并且相对于其他 JAKs 显示出 246 倍的选择性。 -
pan-PAD 抑制剂
Streptonigrin(Bruneomycin),是由 Streptomyces flocculus 产生的天然产品,具有抗肿瘤和抗菌活性。Streptonigrin 作为一种 pan-PAD 抑制剂,其 IC50 分别为 PAD1 的 48.3±34.2 μM、PAD2 的 26.1±0.3 μM、PAD3 的 0.43±0.03 μM 和 PAD4 的 2.5±0.4 μM。 -
HDAC 抑制剂
MPT0E028 是一种口服活性且选择性的 HDAC 抑制剂,其 IC50 分别针对 HDAC1、HDAC2 和 HDAC6 为 53.0 nM、106.2 nM 和 29.5 nM。 -
BRM/BRG1 ATP 抑制剂
BRM/BRG1 ATP Inhibitor-1 是一种 异构双重 针对 钙钛矿同源体 (BRM)/SWI/SNF 相关基质相关肌动蛋白依赖性染色质调节亚家族 A 成员 2 (SMARCA2) 和 钙钛矿相关基因 1 (BRG1)/SMARCA4 ATP酶活性抑制剂,两者的 IC50 值均低于 0.005 μM。 -
Tankyrase 抑制剂
Tankyrase-IN-2(化合物5k)是一种高效、选择性且可口服活性的tankyrase抑制剂(分别对TNKS1、TNKS2以及PARP1的IC50为10、7和710 nM)。 -
LIN28 抑制剂
LIN28 抑制剂 LI71 是一种有效且能够渗透细胞的 LIN28 抑制剂,它能够消除 LIN28 介导的寡聚尿苷化作用,IC50 值为 7 uM。 -
PRMT 抑制剂
GSK3368715 (EPZ019997) 是一种口服活性、可逆的、与S-腺苷-L-甲硫氨酸(SAM)非竞争性的 I型蛋白精氨酸甲基转移酶(PRMTs)抑制剂(IC50=3.1 nM (PRMT1), 48 nM (PRMT3), 1148 nM (PRMT4), 5.7 nM (PRMT6), 1.7 nM (PRMT8))。 -
BET bromodomain 抑制剂
Bromodomain inhibitor-8(中间体21)是一种用于治疗自身免疫和炎症性疾病的 BET bromodomain 抑制剂。 -
JAK 抑制剂
Delgocitinib 是一种新型且特异性的 JAK 抑制剂,其 IC50 分别针对 JAK1、JAK2、JAK3 和 Tyk2 为 2.8、2.6、13 和 58 nM。