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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G9a inhibitor
CPUY074020 is a potent G9a inhibitor with an IC50 of 2.18 μM, and possesses anti-proliferative activity . -
Dot1L inhibitor
Dot1L-IN-1 is a highly potent, selective and structurally novel Dot1L inhibitor with a Ki of 2 pM. -
DNMT inhibitor
SGI-110 is a second generation DNA-hypomethyating agent.- Sho Sato, .et al. , Sci Rep, 2023, Jan 27;13(1):1537 PMID: 36707610
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HDACs/mTOR Inhibitor 1
HDACs/mTOR Inhibitor 1 is a dual Histone Deacetylases (HDACs) and mammalian target of Rapamycin (mTOR) target inhibitor for treating hematologic malignancies. - GSK 525768A is the enantiomer compound of GSK 525762A, which is a potent small molecule inhibitor that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4); GSK 525768A has NO activity towards BET.
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Aurora Kinase inhibitor
SAR156497 is an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy with IC50 = 0.5 nM (Aurora A), 1 nM (Aurora B / incenp), 3 nM (Aurora C / incenp) respectively SAR156497 combines high in vitro potency with satisfactory metabolic stability and limited CYP3A4 and PDE3 inhibition. -
Pan-PIM kinase inhibitor
LGB-321 HCl is a potent and selective ATP-competitive small molecule inhibitor of PIM kinases (Pan-PIM kinase inhibitor).- 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
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JAK2 inhibitor
NS-018 hydrochloride is a novel highly selective JAK2 inhibitor. -
LSD1 inhibitor
T-3775440 (hydrochloride) is an irreversible lysine-specific histone demethylase (LSD1) inhibitor with an IC50 value of 2.1 nM. -
fluorescent substrate for HDAC
Ac-Lys-AMC (Hexanamide), also termed MAL, is a fluorescent substrate for histone deacetylase HDACs. -
p300/CBP histone acetyltransferase inhibitor
P300/CBP-IN-3, a p300/CBP histone acetyltransferase inhibitor. -
SMYD3 inhibitor
SMYD3-IN-1 (compound 29) is an irreversible and selective inhibitor of SMYD3 (SET and MYND domain containing 3), with an IC50 of 11.7 nM. -
PARP14 inhibitor
PARP14 inhibitor H10, compound H 10, is a selective inhibitor against PARP14 (IC50=490 nM), over other PARPs (??24 fold over PARP1). PARP14 inhibitor H10 induces caspase-3/7-mediated cell apoptosis. -
SUV39H2 inhibitor
OTS186935 is a protein methyltransferase SUV39H2 inhibitor with an IC50 of 6.49 nM.- Jennings Luu, .et al. , Hum Mol Genet, 2020, Jul 21;ddaa158 PMID: 32691052
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BRD4-BD1 inhibitor
BRD4 Inhibitor-10 is a potent BRD4-BD1 inhibitor extracted from patent WO2015022332A1, Compound II-25, has an IC50 of 8 nM. -
Bromodomain inhibitor
Bromodomain IN-1 is a Bromodomain inhibitor extracted from patent WO2016069578A1, compound 4 . -
HDAC inhibitor
CHDI-390576, a potent, cell permeable and CNS penetrant class IIa histonedeacetylase (HDAC) inhibitor with IC50s of 54 nM, 60 nM, 31 nM, 50 nM for class IIa HDAC4, HDAC5, HDAC7, HDAC9, respectively, shows >500-fold selectivity over class I HDACs (1, 2, 3) and ~150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. -
JAK3 covalent inhibitor
JAK3 covalent inhibitor-1 is a potent and selective janus kinase 3 (JAK3) covalent inhibitor with an IC50 of 11 nM and shows 246-fold selectivity vs other JAKs.