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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HDAC 抑制剂
Valproic acid sodium salt (Sodium Valproate) 是一种 HDAC 抑制剂,其 IC50 在 0.5 至 2 mM 范围内,同时抑制 HDAC1(IC50,400 μM),并诱导 HDAC2 的蛋白酶体降解。 -
HDAC 抑制剂
Trichostatin A(TSA)抑制 HDACs 1, 3, 4, 6 和 10,其 IC50 值约为 20 nM。- Thibaud Reyser, .et al. , Pharmaceutics, 2023, Oct 10;15(10):2440 PMID: 37896200
- Goudreault M, .et al. , Research Square, 2021, 22 Nov
- Hiroyuki Imuta, .et al. , Heart Vessels, 2020, Jul 16 PMID: 32676696
- M??ndez-Blanco C, .et al. , Cancers (Basel), 2019, Dec 9;11(12). pii: E1984 PMID: 31835431
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HDAC 抑制剂
Vorinostat 是一种 HDACs 抑制剂,它抑制去乙酰化作用,导致 高乙酰化组蛋白 和转录因子的积累。- Masahiro Yamada, .et al. , Int J Hematol, 2024, Sep;120(3):325-336 PMID: 38954186
- Amy E Neely, .et al. , Commun Biol, 2023, Jun 23;6(1):664 PMID: 37353594
- Ting-Yu Chang, .et al. , Biomed Pharmacother, 2021, Jun;138:111485 PMID: 33740521
- David Diaz-Carballo, .et al. , Commun Biol, 2021, Mar 3;4(1):276 PMID: 33658617
- Arshdeep Singh, .et al. , Eur J Med Chem, 2021, Apr 5;215:113169 PMID: 33588178
- Shariful Islam, .et al. , Blood Adv, 2020, 4(20): 5297-5310 PMID: 33108458
- Giovanni Bocci, .et al. , ACS Pharmacol Transl Sci, 2020, Oct 14
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Aurora Kinase 抑制剂
VX-680 是一种强效且选择性的小分子Aurora激酶抑制剂。- Helen E. Grimsley, .et al. , bioRxiv, 2024, Jan 23
- Sakamoto K, .et al. , Leukemia, 2018, May 23 PMID: 29795241
- W. Joost Lesterhuis, .et al. , Sci Rep, 2015, 5: 12298 PMID: 26193793
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PARP 抑制剂
XAV 939 是一种 TNKS 抑制剂(对于 TNKS1 和 TNKS2 的 IC50 值分别为 0.011 和 0.004 微米)。- Shizu Aikawa, .et al. , EMBO J, 2017, Jul 14; 36(14): 2146-2160 PMID: 28588064
- Mikaël M. Martino, .et al. , Nat Commun, 2016, 7: 11051 PMID: 27001940
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PARP 抑制剂
MK-4827 是一种新型的、高效的、口服生物利用度高的 PARP-1 和 PARP-2 抑制剂。- Joseph M Gozgit, .et al. , Cancer cell, 2021, Jul 22;S1535-6108(21)00340-8 PMID: 34375612
- Ann-Katrin Hopp, .et al. , Molecular cell, 2021, Jan 21; 81(2): 340–354 PMID: 33450210
- Bian C, .et al. , Nat Commun, 2019, Feb 11;10(1):693 PMID: 30741937
- Tahira Baloch, .et al. , BMC Cancer, 2019, Jan 10;19(1):44 PMID: 30630446
- Khalid Hilmi, .et al. , Sci Adv, 2017, May; 3(5): e1601898 PMID: 28560323
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HDAC 抑制剂
AR-42 是一种新型的 HDAC 抑制剂,通过下调始终处于激活状态的 Kit,对恶性肥大细胞系显示出生物活性。- Yong-Hui Liao, .et al. , Mol Med Rep, 2018, Feb; 17(2): 2803-2810 PMID: 29257262
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JAK1/2 抑制剂
INCB018424 是一种强效且选择性的 Janus-associated kinase (JAK) 1 和 2 抑制剂,其半抑制浓度(IC50)分别为 JAK1 2.7 nM、JAK2 4.5 nM 和 JAK3 332 nM。- Meenu Kesarwani, .et al. , Blood Adv, 2024, Jun 11;8(11):2765-2776 PMID: 38531054
- Aya Hasan Alshammari, .et al. , Biochem Pharmacol, 2022, Mar;197:114914 PMID: 35041812
- Daniel Doheny, .et al. , Oncogene, 2020, Oct;39(42):6589-6605 PMID: 32929154
- Rasmus Siersbek, .et al. , Cancer cell, 2020, Jul 6;S1535-6108(20)30311-1 PMID: 32679107
- Brittany M. Duggan, .et al. , Sci Rep, 2017, 7: 1578 PMID: 28484277
- Fujita KI, .et al. , J Pharm Sci, 2017, Sep;106(9):2632-2641 PMID: 28479358
- Kagoya Y, .et al. , Blood., 2014, Nov 6;124(19):2996-3006 PMID: 25217696
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HDAC6 抑制剂
Tubastatin A 是一种强效且选择性的 HDAC6 抑制剂,在无细胞试验中的 IC50 为 15 nM。它对所有其他同工酶具有1000倍的选择性,除了 HDAC8(57倍)。- Isin Cakir, .et al. , Nat Metab, 2022, Jan;4(1):44-59 PMID: 35039672
- Isin Cakir, .et al. , Elife, 2022, Mar 24 PMID: 35323110
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JAK2/FLT3 抑制剂
TG-101348 是一种口服生物利用度高的、ATP竞争性的、选择性的 Janus-associated kinase 2 抑制剂,具有潜在的抗肿瘤活性。 -
PI3K/HDAC 抑制剂
CUDC-907(Fimepinostat)是一种小分子抑制剂,能够同时针对PI3K和HDAC。CUDC-907比单一的PI3K抑制剂、HDAC抑制剂或这两种单一药物的最大耐受剂量组合更有效。- Bopei Cui, .et al. , Signal Transduct Target Ther, 2023, Sep 25;8(1):366 PMID: 37743418
- Caner Gunayd?n, .et al. , Immunopharmacol Immunotoxicol, 2022, Jun;44(3):447-455 PMID: 35291899
- Chie Ishikawa, .et al. , Eur J Haematol, 2020, Eur J Haematol PMID: 32780889
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Aurora Kinase B/C 抑制剂
GSK1070916 是一种强效的 Aurora B/C 激酶抑制剂(IC50 为 3.5 nM/6.5 nM),在组织培养细胞和人类肿瘤异种移植模型中具有广泛的抗肿瘤活性。 -
Aurora A/B Kinase 抑制剂
PF-03814735 是一种新型、高效、可逆的 Aurora A/B 抑制剂,其 IC50 分别为 0.8 nM/5 nM,对 Flt3、FAK、TrkA 的抑制作用较弱,对 Met 和 FGFR1 几乎无活性。目前处于第一阶段临床试验。 -
PARP 抑制剂
BMN-673 是一种口服生物利用度的抑制剂,针对核酶多聚(ADP-核糖)聚合酶(PARP)具有潜在的抗肿瘤活性。- Subhajit Chatterjee, .et al. , J Cancer Res Clin Oncol, 2022, Dec;148(12):3521-3535 PMID: 35962813
- Charles-André Philip, .et al. , BMC Cancer, 2017, 17: 638 PMID: 28886696
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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。 -
JAK 抑制剂
Baricitinib,也被称为INCB028050或LY3009104,是一种选择性的口服生物利用度的JAK1/JAK2抑制剂,对JAK1(5.9 nM)和JAK2(5.7 nM)具有纳摩尔级的效力。- Hongli Liu, .et al. , Adv Rheumatol, 2023, Aug 28;63(1):45 PMID: 37641106
- Dandan Wang, .et al. , Adv Rheumatol, 2023, May 16;63(1):22 PMID: 37194022
- Yuki Sasaki, .et al. , JCI Insight, 2022, Apr 8;7(7) PMID: 35393946
- Yutian Lei, .et al. , Kidney Int, 2021, Feb 16 PMID: 33607177
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Aurora A Kinase 抑制剂
MK-5108,亦称为 VX-689,是一种与 ATP结合位点 竞争的 aurora A激酶 抑制剂。- Wei TW, .et al. , Cancer Res, 2017, Jan 15;77(2):494-508 PMID: 28069801
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MGMT 抑制剂
O6BTG-octylglucoside 是一种强效的 O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)抑制剂,其 IC50 在体外(细胞提取物)为32纳摩尔,而在HeLa S3细胞中为10纳摩尔。 -
BET 抑制剂
GSK-525762A 是一种针对 BET (Bromodomain and Extra-Terminal) 家族的小分子抑制剂。 -
JAK1/2 抑制剂
Ruxolitinib sulfate(INCB018424 sulfate)是首个进入临床的强效、选择性 JAK1/2 抑制剂,其 IC50 值分别为 3.3 nM/2.8 nM,并且对 JAK1/2 比 JAK3 的选择性高出 130 倍以上。 -
LKB1/AAK1 dual 抑制剂
Pim1/AKK1-IN-1 是一种强效的多濼酶抑制剂,其 Kd 值分别为针对 Pim1、AKK1、MST2、LKB1 的 35 nM/53 nM/75 nM/380 nM,同时也能抑制 MPSK1 和 TNIK。 -
JAK 抑制剂
磷酸鲁索替尼是鲁索替尼的磷酸盐形式,这是一种口服生物可用的Janus相关激酶(JAK)抑制剂,具有潜在的抗肿瘤和免疫调节活性。 -
EZH2 抑制剂
GSK126 是一种高效、高选择性的 S-腺苷甲硫氨酸竞争性小分子抑制剂,针对 EZH2 甲基转移酶活性,能够降低全局 H3K27me3 水平并重新激活被沉默的 PRC2 目标基因。- Lucy E. Dawson, .et al. , Sarcoma, 2020, 2020: 8647981 PMID: 32300280
- Hirosumi Tamura, .et al. , Oncol Rep, 2018, Aug; 40(2): 635-646 PMID: 29917168
- Dupret B, .et al. , Biochim Biophys Acta Gene Regul Mech, 2017, Oct;1860(10):1079-1093 PMID: 28887218
- Theresa Baker, .et al. , Oncotarget, 2015, Oct 20; 6(32): 32646-32655 PMID: 26360609
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BET Bromodomain 抑制剂
GSK1210151A 是一种新型选择性抑制剂,针对溴结构域和额外末端(BET)家族蛋白 BRD2、BRD3 和 BRD4。- Momeny M, .et al. , Anticancer Drugs, 2018, Nov;29(10):1011-1020 PMID: 30096128
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JAK2 抑制剂
WP1066 是一种新型的 JAK2 抑制剂,它能抑制携带 JAK2 V617F 突变的红细胞人类细胞的增殖,并诱导凋亡。- Simona Moravcova, .et al. , Life (Basel), 2021, Oct 18;11(10):1105 PMID: 34685476
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HDAC 抑制剂
Romidepsin 强烈抑制 HDAC1 和 HDAC2,其 IC5N/A 分别为 1.6 nM 和 3.9 nM,但在抑制 HDAC4 和 HDAC6 方面相对较弱,其 IC5N/A 分别为 25 nM 和 79N/A nM。- Dan Lu, .et al. , Sci Adv, 2024, Oct 25;10(43):eadp2229 PMID: 39454005
- Yu-Fang Liu, .et al. , J Biochem Mol Toxicol, 2022, Jun;36(6):e23044 PMID: 35499365
- David Diaz-Carballo, .et al. , Commun Biol, 2021, Mar 3;4(1):276 PMID: 33658617
- Eva Hesping, .et al. , Int J Parasitol Drugs Drug Resist, 2020, 14: 249-256
- Shariful Islam, .et al. , Blood Adv, 2020, 4(20): 5297-5310 PMID: 33108458
- Elena Netchiporouk, .et al. , Oncotarget, 2017, Nov 10; 8(56): 95981-95998 PMID: 29221181
- Ivan V. Litvinov, .et al. , Clin Cancer Res, 2014, 20(14): 3799-3808 PMID: 24850846
- Ivan V Litvinov, .et al. , Cell Cycle., 2014, 15; 13(18): 2975-2982 PMID: 25486484
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HDAC6 抑制剂
ACY-1215 选择性地靶向并结合到 HDAC6,通过 Hsp90 的过度乙酰化干扰 Hsp90 蛋白质伴侣系统,并阻止随后的聚集体蛋白质降解。 -
Pim 抑制剂
SIM-4a 是一种 Pim 激酶抑制剂,通过激活 AMPK 来阻断 mTORC1 活性。主要针对 Pim-2,对其他丝氨酸/苏氨酸激酶或酪氨酸激酶的抑制作用不显著。- Liong S, .et al. , Placenta, 2017, May;53:101-112 PMID: 28487013
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FLT3 抑制剂
TG-02 是一种新型小分子,具有强大的 CDK/JAK2/FLT3 抑制作用。 -
Pim 抑制剂
TCS PIM-1 4a 是一种选择性的、与ATP竞争的Pim激酶抑制剂(IC50 值分别为24 nM和100 nM,针对Pim-1和Pim-2)。