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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BRD 抑制剂
L-45 是首个具有高效、选择性和细胞活性的 p300/CBP-associated factor (PCAF) bromodomain (Brd) 抑制剂,其 Kd 值为 126±15 nM。 -
SHP2 抑制剂
SHP099 是一种效力强大、选择性高、可口服的 SHP2 抑制剂,其 IC50 为 70 nM。- Majid Momeny, .et al. , EMBO Mol Med, 2024, Jun 17 PMID: 38886591
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BET bromodomain 抑制剂
PROTAC BET-binding moiety 2 是一种 BET bromodomain 抑制剂。 -
PTP1B/IKK-β抑制剂 and dual PPARα and PPARβ 激动剂
Ertiprotafib 是一种 PTP1B 抑制剂、IkB激酶β (IKK-β) 抑制剂,以及 PPARα 和 PPARβ 的双重激动剂,其对 PTP1B 的半抑制浓度(IC50)为1.6 μM,对 IKK-β 的IC50为400 nM,对 PPARα/PPARβ 的半有效浓度(EC50)约为1 μM。 -
miR-210 抑制剂
Targapremir-210 是一种强效的 miR-210 抑制剂,在 MDA-MB-231 细胞中的 IC50 为 200 nM。Targapremir-210 绑定到 miR-210 发夹前体的 Dicer 位点。这种相互作用抑制了成熟 miRNA 的产生。 -
MicroRNA 抑制剂
MIR96-IN-1 是一种选择性抑制 microRNA-96 生物生成的抑制剂。它通过上调一个蛋白质靶点(FOXO1)并在癌细胞中诱导凋亡来发挥作用。 -
ATP-competitive multitargeted kinase 抑制剂
Ilorasertib (ABT-348) 是一种强效且与ATP竞争的多靶点激酶抑制剂,它能抑制 Aurora C、Aurora B 和 Aurora A,其半抑制浓度(IC50)分别为1纳摩尔、7纳摩尔和120纳摩尔。 -
HDAC1 抑制剂
Domatinostat tosylate(4SC-202)是一种选择性的I类HDAC抑制剂,其IC50分别为HDAC1的1.20 μM、HDAC2的1.12 μM和HDAC3的0.57 μM。它还显示出对赖氨酸特异性去甲基化酶1(LSD1)的抑制活性。 -
SIRT1 activator
SRT 1720 Hydrochloride 是一种选择性的 SIRT1 激活剂,其 EC50 为 0.10 μM,对 SIRT2 和 SIRT3 的活性较弱。 -
PTP1B 抑制剂
PTP1B-IN-3 是一种强效且选择性的 PTP1B 抑制剂,其 IC50 分别为 120 nM(PTP1B)和 120 nM(TCPTP)。 -
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。 -
PARP 抑制剂
Veliparib dihydrochloride 是一种强效的 PARP 抑制剂,分别以 Kis 值 5.2 和 2.9 nM 抑制 PARP1 和 PARP2。 -
EZH2 抑制剂
PF-06821497(化合物23a)是一种强效、选择性且可口服的增强子泽斯特同源物2(EZH2)抑制剂,对突变型Y641N EZH2的Ki值<0.1 nM。展示出强大的肿瘤生长抑制效果。 -
EZH1/2 dual 抑制剂
Valemetostat tosylate(DS-3201 tosylate)是一种首创的 EZH1/2 双重抑制剂,用于研究复发/难治性外周T细胞淋巴瘤。 -
JAK2 抑制剂
NVP-BSK805 dihydrochloride (BSK805 dihydrochloride) 是一种 ATP-竞争性 JAK2 抑制剂,其 IC50 分别为 JAK2 JH1 (JAK 同源域 1) 0.48 nM、JAK1 JH1 31.63 nM、JAK3 JH1 18.68 nM 和 TYK2 JH1 10.76 nM。 -
Pim 抑制剂
INCB053914 磷酸盐是一种从专利 WO 2017044730 A1 提取的 Pim 抑制剂,化合物 1;具有小于 35 nM 的 IC50。 -
HDAC 抑制剂
Givinostat hydrochloride(ITF-2357 hydrochloride)是一种HDAC抑制剂,其对HDAC1和HDAC3的IC50分别为198 nM和157 nM。 - 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)。
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PARP1/PARP2 抑制剂
E7449 是一种强效的 PARP1 和 PARP2 抑制剂,同时也能抑制 TNKS1 和 TNKS2,其半抑制浓度(IC50)分别为 PARP1 2.0 nM、PARP2 1.0 nM、TNKS1 和 TNKS2 约50 nM,使用的底物为 32P-NAD+。 -
multi-targeted kinase 抑制剂
ENMD-2076 Tartrate 是一种多靶点激酶抑制剂,其 IC50 分别为 Aurora A 1.86 nM、Flt3 14 nM、KDR/VEGFR2 58.2 nM、Flt4/VEGFR3 15.9 nM、FGFR1 92.7 nM、FGFR2 70.8 nM、Src 56.4 nM、PDGFRα。 -
BET binding to histones 抑制剂
(R)-BAY1238097 是 BAY1238097 的 R-异构体,具有较低的活性。BAY1238097 是一种强效且选择性的 BET 与组蛋白结合的抑制剂,并且在不同的 AML(急性髓性白血病)和 MM(多发性骨髓瘤)模型中具有强大的抗增殖活性,这是通过下调 c-Myc 水平及其下游转录组实现的。