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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multi-kinase 抑制剂
Cenisertib (AS-703569) 是一种多激酶抑制剂,能够阻断 Aurora-kinase-A/B、ABL1、AKT、STAT5 和 FLT3 的活性。 -
multi-kinase 抑制剂
Lestaurtinib(CEP-701;KT-5555)是一种多激酶抑制剂,对Trk家族的受体酪氨酸激酶具有强大的活性。Lestaurtinib抑制JAK2、FLT3和TrkA的IC50分别为0.9、3和小于25 nM。 -
SMYD2 抑制剂
AZ505 ditrifluoroacetate 是一种强效且高度选择性的 SMYD2 抑制剂(IC50=0.12 uM),具有潜在的抗癌活性,其选择性是 SMYD3(IC50>83.3 uM)、DOT1L(IC50>83.3 uM)、EZH2(IC50>83.3 uM)的600倍以上。 -
Aurora kinase A 抑制剂
TC-A-2317 盐酸盐是一种强效的Aurora kinase A抑制剂(Ki = 1.2 nM,相比之下对Aurora kinase B的抑制为101 nM)。相较于其他60种激酶具有选择性(IC50值 > 1000 nM)。具有良好的细胞渗透性和抗肿瘤活性。 - GSK 525768A 是 GSK 525762A 的对映体化合物,后者是一种强效的小分子抑制剂,能够干扰 BET 家族的溴结构域(Brd2、Brd3 和 Brd4)的功能;GSK 525768A 对 BET 没有活性。
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PARP 抑制剂
BMN-673 (8R,9S) 是 BMN-673 的 (8R,9S) 对映体。BMN 673 是一种新型的 PARP 抑制剂,其 IC50 为 0.58 nM。 -
Mnk2/JAK3 抑制剂
Cercosporamide,一种usnic amide,最初在Cercosporidium henningsii中被发现,作为一种宿主选择性植物毒素和广谱抗真菌剂,它是MAP-kinase interacting kinase-2 (Mnk2; IC50 = 11 nM)、JAK3 (IC50 = 31 nM) 和 Mnk1 (IC50 = 116 nM) 的强效抑制剂。 - 钙调神经磷酸酶抑制肽是一种选择性的钙调蛋白-钙调素依赖性蛋白磷酸酶(钙调神经磷酸酶)抑制剂(IC50约10 uM)。不抑制PP1、PP2A或CaM激酶II(IC50 > 100 mM)。
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HDAC6 抑制剂
TCS HDAC6 20b,是一种选择性的组蛋白去乙酰化酶6(HDAC6)抑制剂。与紫杉醇联合使用时,能抑制HCT116细胞的生长。同时也能抑制由雌激素刺激的MCF-7细胞的生长。 -
Calcineurin/PP2B 抑制剂
Ascomycin 是 tacrolimus (FK506) 的乙基类似物,具有强大的免疫抑制特性。它已被研究用于治疗自身免疫疾病和皮肤病,以及用于预防器官移植后的排斥反应。 -
BET bromodomain 抑制剂
CPI 0610 是一种小分子抑制剂,针对 Bromodomain and Extra-Terminal (BET) 蛋白家族,具有潜在的抗肿瘤活性。 -
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。 -
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。 -
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。 -
KDM2A/7A 抑制剂
KDM2A/7A-IN-1 是首创的、选择性的、细胞渗透性的组蛋白赖氨酸去甲基化酶 KDM2A/7A 抑制剂,对 KDM2A 的 IC50 为 0.16 μM,对其他 JmjC 赖氨酸去甲基化酶具有 75 倍的选择性,并且对甲基转移酶和组蛋白乙酰转移酶无活性。 -
SMYD2 抑制剂
SMYD2-IN-1 是一种从专利 WO2016166186A1 中提取的 SMYD2 抑制剂,化合物示例 1.1,具有 4.45 nM 的 IC50。 -
EHMT 抑制剂
EHMT2-IN-1 是一种强效的 EHMT 抑制剂,对 EHMT1 肽、EHMT2 肽和细胞内 EHMT2 的 IC50 均小于 100 nM。用于血液疾病或癌症的研究。
