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.
-
DNMT 抑制剂
SGI-110 是一种第二代 DNA-去甲基化剂。- Lise Brault, .et al. , EMBO Mol Med, 2025, Aug 29 PMID: 40883610
- Sho Sato, .et al. , Sci Rep, 2023, Jan 27;13(1):1537 PMID: 36707610
-
HDACs/mTOR 抑制剂 1
HDACs/mTOR Inhibitor 1 是一种针对组蛋白去乙酰化酶(HDACs)和哺乳动物雷帕霉素靶蛋白(mTOR)的双重抑制剂,用于治疗血液恶性肿瘤。 -
Pan-PIM kinase 抑制剂
LGB-321 HCl 是一种强效且选择性的 ATP-竞争性小分子抑制剂,专门针对 PIM激酶(全谱PIM激酶抑制剂)。- Ricardo de Matos Simoes, .et al. , Nat Cancer, 2023, May;4(5):754-773 PMID: 37237081
- Andrea L. Casillas, .et al. , Clin Cancer Res, 2018, Jan 1; 24(1): 169-180 PMID: 29084916
-
PARP14 抑制剂
PARP14 抑制剂 H10,化合物 H 10,是一种针对 PARP14 的选择性抑制剂(IC50=490 nM),相较于其他 PARP 抑制效果高出 24 倍以上(??24 倍以上 PARP1)。PARP14 抑制剂 H10 诱导 caspase-3/7 介导的细胞凋亡。 -
SUV39H2 抑制剂
OTS186935 是一种蛋白质甲基转移酶 SUV39H2 抑制剂,其 IC50 为 6.49 nM。- Jennings Luu, .et al. , Hum Mol Genet, 2020, Jul 21;ddaa158 PMID: 32691052
-
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。 -
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)。 -
Aurora 抑制剂
Aurora inhibitor 1 是一种强效的 Aurora 抑制剂,其 IC50 分别为 4 nM 和 13 nM,针对 Aurora A 和 Aurora B 激酶。 -
Dot1L 抑制剂
Dot1L-IN-2 是一种强效、选择性且可口服的 Dot1L (一种组蛋白甲基转移酶) 抑制剂,其 IC50 和 Ki 分别为 0.4 nM 和 0.08 nM。 -
PPI 抑制剂
BRCA1-IN-2(化合物15)是一种细胞渗透性的蛋白-蛋白相互作用(PPI)抑制剂,针对BRCA1,具有 IC50 为0.31 μM和 Kd 为0.3 μM,通过破坏BRCA1 (BRCT)2/蛋白相互作用显示出抗肿瘤活性。 -
BET bromodomain 抑制剂
PROTAC BET-binding moiety 2 是一种 BET bromodomain 抑制剂。 -
antineoplastic activity
Guadecitabine,也被称为SGI-110,是一种通过磷酸二酯键将去柠檬酸与鸟苷连接的二核苷酸抗代谢物,具有潜在的抗肿瘤活性。 - BRD7-IN-1 free base 是 BI7273(BRD7/9 抑制剂)的改良衍生物,通过连接体与 VHL 配体结合,形成 PROTAC VZ185(针对 BRD7/9 的 VZ185,其 DC50 分别为 4.5 和 1.8 nM)。
-
HDAC 抑制剂
Nanatinostat(CHR-3996)是一种强效的、选择性针对类 I并且可口服的组蛋白去乙酰化酶(HDAC)抑制剂,其半抑制浓度(IC50)为8纳摩尔。 -
BET 抑制剂
CPI-0610 羧酸是一种强效的溴结构域和额外末端(BET)蛋白抑制剂。CPI-0610 羧酸在多发性骨髓瘤治疗中具有潜在应用。 -
peptidylarginine deminase (PAD) 抑制剂
Cl-amidine TFA 是一种口服活性的肽基精氨酸脱亚胺酶(PAD)抑制剂,其 IC50 值分别为 PAD1 的 0.8 μM、PAD3 的 6.2 μM 和 PAD4 的 5.9 μM。
