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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ETA-receptor Antagonist
Zibotentan (ZD4054)is an orally administered, potent and specific ETA-receptor (endothelin A receptor) antagonist (IC50 = 21 nM).- Tony Ngo, .et al. , Nat Chem Biol, 2017, Feb; 13(2): 235-242 PMID: 27992882
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EndothelinA receptor antagonist
Ambrisentan functions as an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA).- Naoki Dohi, .et al. , PLoS One, 2021, 16(8): e0255656 PMID: 34343209
- Tony Ngo, .et al. , Nat Chem Biol, 2017, Feb; 13(2): 235-242 PMID: 27992882
- Toshiaki Okamoto, .et al. , World J Hepatol, 2016, Aug 8; 8(22): 933-941 PMID: 27574547
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Endothelin antagonist
Avosentan (SPP301) is a potent and highly selective ETA receptor blocker. -
Endothelin receptor antagonist
Macitentan is an orally active, non-peptide dual endothelin ETA and ETB receptor antagonist for the potential treatment of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). -
ETA receptor antagonist
Sitaxentan sodium (TBC-11251) is a selective endothelin receptor-A antagonist with IC50 and Ki of 1.4 nM and 0.43 nM, respectively. -
ETA receptor antagonist
Sitaxsentan (IPI 1040; TBC-11251) is a selective endothelin A (ETA) receptor antagonist. Antihypertensive. Sitaxsentan is used in treatment of chronic heart failure. -
endothelin receptor modulator
Endothelin Mordulator 1 is a endothelin receptor modulator, used for the research of endothelin-mediated disorders. -
ETA antagonist
Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer, including non-small cell lung cancer. It is an endothelin receptor antagonist selective for subtype A (ETA). - Endothelin-2, human, endogenous peptide found predominately in the kidney and intestine. Displays similar selectivity for ETA and ETB endothelin receptors.
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ET-A and ET-B antagonist
Bosentan is an endothelin (ET) receptor antagonist for ET-A and ET-B with Ki of 4.7 nM and 95 nM, respectively. -
Endothelin antagonist receptor
Atrasentan hydrochloride is an endothelin antagonist receptor (IC50=0.0551 nM, ETA) being developed for the treatment of prostate cancer. -
ETA antagonist
ETA antagonist 1 is a ETA selective antagonist with an IC50 of 0.08 μM. - Aminaftone, a derivative of 4-aminobenzoic acid, downregulates endothelin-1 (ET-1) production in vitro by interfering with the transcription of the pre-pro-ET-1 gene.
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angiotensin II and endothelin A receptor antagonist
Sparsentan (RE-021) is a highly potent dual angiotensin II and endothelin A receptor antagonist with Kis of 0.8 and 9.3 nM, respectively. -
endothelin (ET) receptor antagonist
Tezosentan (RO 610612) is an endothelin (ET) receptor antagonist, with pA2s of 9.5, 7.7 for ETA and ETB receptors, respectively. -
endothelin A (ETA) receptor antagonist
Darusentan is a selective endothelin A (ETA) receptor antagonist. -
endothelin ETA and ETB receptor antagonist
Macitentan n-butyl analogue is a n-butyl analogue of Macitentan. Macitentan is an orally active, non-peptide dual endothelin ETA and ETB receptor antagonist for the potential treatment of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). -
dual ETA/ETB antagonist
Aprocitentan (ACT-132577) is the major and pharmacologically active metabolite of Macitentan. Aprocitentan is dual ETA/ETB antagonist with IC50s of 3.4 nM and 987 nM, and pA2 valus of 6.7 and 5.5, respectively.