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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KDM inhibitor
2,4-Pyridinedicarboxylic Acid (2,4-PDCA) is an inhibitor of histone lysine-specific demethylases that targets on JMJD2A (KDM4A), KDM4C, KDM4E (IC50, 1.4 μM), KDM5B (IC50, 3 μM), KDM6A and other 2-oxogynases. -
KDM2/7 inhibitor
TC-E 5002, selective histone demethylase KDM2/7 subfamily inhibitor (IC50 values are 0.2, 1.2, 6.8, 55, 83, >100 and >120 uM for KDM7A, KDM7B, KDM2A, KDM5A, KDM4C, KDM6A and KDM4A respectively). Inhibits growth of HeLa and KYSE-150 cancer cells in vitro. -
PRMT6 inhibitor
EPZ020411 is a potent and selective inhibitor of PRMT6 with IC50 of 10 nM, has >10 fold selectivity for PRMT6 over PRMT1 and PRMT8.- Tianzhi Huang, .et al. , Mol Cell, 2021, Mar 18;81(6):1276-1291 PMID: 33539787
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HDAC6 inhibitor
CAY10603 is a potent and selective HDAC6 inhibitor with IC50 of 2 pM, >200-fold selectivity over other HDACs.- Isin Cakir, .et al. , Nat Metab, 2022, Jan;4(1):44-59 PMID: 35039672
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PARP1/PARP2 inhibitor
Niraparib tosylate (MK-4827 tosylate) is a highly potent and orally bioavailable PARP1 and PARP2 inhibitor with an IC50 of 3.8 and 2.1 nM, respectively.- Laurie B Schenkel, .et al. , Cell Chem Biol, 2021, Mar 2;S2451-9456(21)00095-7 PMID: 33705687
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JAK inhibitor
Oclacitinib maleate (PF-03394197 maleate) is a novel JAK inhibitor. Oclacitinib maleate (PF-03394197 maleate) is most potent at inhibiting JAK1 (IC50=10 nM).- Carlos H de Mello Souza, .et al. , Vet Dermatol, 2021, Dec 9 PMID: 34882871
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HDAC/ER stress inhibitor
Sodium phenylbutyrate is an inhibitor of HDAC and endoplasmic reticulum (ER) stress, used in cancer and infection research. -
HDAC6 inhibitor
Tubastatin A is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in a cell-free assay, and is selective (1000-fold more) against all other isozymes except HDAC8 (57-fold more). -
JAK3 inhibitor
PF-06651600 is a potent and irreversible JAK3-selective inhibitor with an IC50 of 33.1 nM but without activity (IC50 > 10 000 nM) against JAK1, JAK2, and TYK2. -
Pim inhibitor
PIM447 is a novel pan-PIM kinase inhibitor with Ki values of 6 pM, 18 pM, 9 pM for PIM1, PIM2, PIM3 respectively. It also inhibits GSK3β, PKN1, and PKCτ, but at a significantly lower potency with IC50 between 1 and 5 μM (>105-fold differential relative to the Ki on PIMs). -
BRD4 Inhibitor
ARV-825 is a hetero-bifunctional molecule that is composed of a BRD4 binding moiety joined to an E3 ligase cereblon binding moiety using proteolysis targeting chimera (PROTAC) technology.- Aidan L Forberg, .et al. , Ann Hematol, 2024, Jan;103(1):199-209 PMID: 37792064
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PRMT5 inhibitor
PF-06855800 (PF06855800) is a potent, selective, SAM competitive, BBB-penetrant, orally active inhibitor of protein arginine methyltransferase PRMT5 with Ki of 0.02 nM. -
Histone Methyltransferase inhibitor
JNJ-64619178 is a PRMT5 inhibitor with high selectivity and potency (subnanomolar range, PRMT5-MEP-50 IC50=0.14 nM) under different in vitro and cellular conditions, paired with favorable pharmacokinetics and safety properties. -
PRMT5 inhibitor
GSK3326595 is a potent, selective, reversible inhibitor of protein arginine methyltransferase 5 (PRMT5) with an IC50 of 6.2 nM. -
BET inhibitor
BAY1238097 is a potent and selective BET inhibitor. BAY1238097 binds to the acetylated lysine recognition motifs on the BRD of BET proteins, thereby preventing the interaction between BET proteins and histones. -
PIM kinases inhibitor
AZD1208 hydrochloride is a novel, orally bioavailable, highly selective PIM kinases inhibitor. -
EZH2 inhibitor
PF-06726304 is a potent and SAM-competitive EZH2 (Enhancer of Zeste Homolog 2) lysine methyltransferase inhibitor. -
SIRT 6 inhibitor
OSS-128167, also known as SIRT6-IN-1, is a potent and selective SIRT 6 inhibitor with IC50 value of 89 μM. -
HDAC8 inhibitor
HDAC8-IN-1, is a HDAC8 inhibitor with an IC50 of 27.2 nM in cancer cell lines. -
SIRT2 inhibitor
Thiomyristoyl is a potent and specific SIRT2 inhibitor with an IC50 of 28 nM. -
JAK1 and TYK2 inhibitor
PF-06700841 is an inhibitor of JAK1 and TYK2 kinases. CAS: 1883299-62-4 (free base) -
BET inhibitor
Mivebresib, also known as ABBV-075, is a potent BET inhibitor (bromodomain (BRD)-containing proteind) with potential antineoplastic activity. -
JAK3/2/1 inhibitor
Tofacitinib is an orally available JAK3/2/1 inhibitor with IC50s of 1, 20, and 112 nM, respectively.- Aya Hasan Alshammari, .et al. , Biochem Pharmacol, 2022, Mar;197:114914 PMID: 35041812
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HDAC inhibitor
Valproic acid is an HDAC inhibitor, with IC50 in the range of 0.5 and 2 mM, also inhibits HDAC1 (IC50, 400 μM), and induces proteasomal degradation of HDAC2; Valproic acid sodium salt is used in the treatment of epilepsy, bipolar disorder and prevention of migraine headaches.- Dan Zhao, .et al. , Poult Sci, 2022, Mar; 101(3): 101642 PMID: 35016046
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HDAC inhibitor
Tucidinostat is a potent and orally bioavailable HDAC enzymes class I (HDAC1/2/3) and class IIb (HDAC10) inhibitor, with IC50s of 95, 160, 67 and 78 nM, less active on HDAC8 and HDAC11 (IC50s, 733 nM, 432 nM, respectively), and shows no effect on HDAC4/5/6/7/9. -
PTP inhibitor
Sodium stibogluconate (Stibogluconate trisodium nonahydrate) is a potent inhibitor of protein tyrosine phosphatase. Sodium stibogluconate inhibits 99% of SHP-1, SHP-2 and PTP1B activity at 10, 100, 100 μg/mL, respectively.

