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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Pdia3/ERp57 activator, STAT3 inhibitor
Diosgenin glucoside, a saponin compound extracted from Tritulus terrestris L., provides neuroprotection by regulating microglial M1 polarization. Diosgenin glucoside protects against spinal cord injury by regulating autophagy and alleviating apoptosis . -
Histone demethylase inhibitor
GSK J1 is a potent and selective inhibitor of the H3K27 histone demethylases JMJD3 and UTX- Nicolas A Fraunhoffer, .et al. , EBioMedicine, 2023, Jun;92:104602 PMID: 37148583
- Guang Bai, .et al. , Epigenetics of Chronic Pain, 2019, Pages 1-48
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Menin-MLL interaction inhibitor
MI-2 (Menin-MLL inhibitor 2) specifically binds to Menin and inhibits Menin??s interaction with MLL fusion proteins in cells. It can effectively reverse MLL fusion protein?Cmediated leukemic transformation by downregulating the expression of target genes downstream of MLL fusion protein oncogenic activity. MI-2 is a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of Menin as an oncogenic cofactor of MLL fusion proteins. -
PAD4 inhibitor
GSK484 hydrochloride (GTPL8577) is a selective and reversible peptidylarginine deiminase 4 (PAD4) inhibitor. -
BET bromodomain Inhibitor
CPI203 is a novel potent, selective and cell permeable inhibitor of the bromodomain and extra terminal (BET) family protein BRD4 with an IC50 of ~37 nM (BRD4 α-screen assay).- Derenzini E, .et al. , Cell Rep, 2018, Aug 21;24(8):2155-2166 PMID: 30134175
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IGF-1R, Aurora, FGFR, ABL, SRC inhibitor
XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1-3, ABL and SRC family kinases. XL228 is an Aurora A inhibitor (IC50, f3 nmol/L) that has shown potent biochemical activity against ABL1 (Ki, 5 nmol/L), as well as the BCR-ABL1 T315I (Ki, 1.4 nmol/L) kinases. -
JAK1 inhibitor
PF-03394197 (oclacitinib) is a potent JAK1 inhibitor- Steven E. Davison, .et al. , PLoS One, 2022, Oct 18;17(10):e0276333 PMID: 36256616
- Banovic F, .et al. , Vet Dermatol, 2018, Nov 12 PMID: 30417482
- Nicholas B, .et al. , J Allergy Clin Immunol, 2017, Jul;140(1):309-312.e4 PMID: 28259448
- Fukuyama T, .et al. , J Pharmacol Exp Ther., 2015, Sep;354(3):394-405 PMID: 26159873
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EZH2 inhibitor
GSK343 is a potent histone H3-lysine 27 (H3K27) methyltransferase EZH2 inhibitor (IC= 4 nM). Diplays 1000-fold selectivity for other HMTs except EZH1 (60-fold selectivity). GSK343 inhibits H3K27 methylation in HCC1806 cells with an IC of <200nM (measured by immunofluorescence).- Yang PM, .et al. , Am J Cancer Res, 2019, Oct 1;9(10):2120-2139 PMID: 31720078
- Nie L, .et al. , Nat Commun, 2019, Nov 8;10(1):5114 PMID: 31704972
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HDAC inhibitor
RG2833 ( is a brain-penetrant HDAC inhibitor with IC50 of 60 nM and 50 nM for HDAC1 and HDAC3. -
JAK1 inhibitor
GLPG0634 is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) being developed by Galapagos for the treatment of rheumatoid arthritis and potentially other inflammatory diseases.- Keisuke Nishimura, .et al. , Arthritis Rheumatol., 2015, Apr;67(4):893-902 PMID: 25545152
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bromodomain inhibitor
Bromosporine is a broad spectrum inhibitor for bromodomains with IC50 of 0.41 μM, 0.29 μM, 0.122 μM and 0.017 μM for BRD2, BRD4, BRD9 and CECR2, respectively. -
SMYD2 inhibitor
AZ505 ditrifluoroacetate is a potent and highly selective inhibitor of the oncogenic protein SMYD2(IC50=0.12 uM) with potential anticancer activity, >600 fold than SMYD3(IC50>83.3 uM); DOT1L(IC50>83.3 uM);EZH2(IC50>83.3 uM). -
pan-Pim kinase inhibitor
AZD1208 is orally available, small molecule inhibitor of PIM kinases with potential antineoplastic activity.- Corbin C Jensen, .et al. , J Cell Biol, 2023, Jun 5;222(6):e202208136 PMID: 37042842
- Jeremiah J Bearss, .et al. , EMBO Rep, 2021, Apr 7;22(4):e50835 PMID: 33586867
- Remy J, .et al. , Biochim Biophys Acta Mol Cell Res, 2019, Feb;1866(2):175-189 PMID: 30389373
- Andrea L. Casillas, .et al. , Clin Cancer Res, 2018, Jan 1; 24(1): 169-180 PMID: 29084916
- Jin H. Song, .et al. , Mol Cancer Ther, 2018, Dec;17(12):2710-2721 PMID: 30190422
- Sathish K.R. Padi, .et al. , Oncotarget, 2017, May 2; 8(18): 30199-30216 PMID: 28415816
- Lim R, .et al. , Mol Hum Reprod, 2017, Jun 1;23(6):428-440 PMID: 28333279
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HDAC3 inhibitor
RGFP966 is an HDAC3 inhibitor with IC50 of 0.08 μM, exhibits > 200-fold selectivity over other HDAC.- Vijaya Bharti, .et al. , Cell Rep, 2022, Dec 20;41(12):111826 PMID: 36543138
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CBP/p300 bromodomain inhibitor
SGC-CBP30 is a potent and selective inhibitor of CREBBP (CBP) and EP300; which are general transcriptional co-activators.- Kevin Bohm, .et al. , Arch Pharm (Weinheim), 2023, Jul;356(7):e2200661 PMID: 37196427
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human A3 adenosine receptor antagonist /Aurora inhibitor
Reversine is a potent human A3 adenosine receptor antagonist with Ki of 0.66 μM, and a pan-aurora A/B/C kinase inhibitor with IC50 of 12 nM/13 nM/20 nM, respectively. Also used for stem cell dedifferentiation.- Amy H. Ide, .et al. , Mol Biol Cell, 2023, Jun 1;34(7):ar76 PMID: 37126397
- Hazheen K, .et al. , J Biol Chem, 2020, August 20
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LSD1/BHC110 & MAO inhibitor
Tranylcypromine hydrochloride is a non-selective MAO-A/B inhibitor. -
JAK2/HDAC dual inhibitor
JAK/HDAC-IN-1 is a potent JAK2/HDAC dual inhibitor, exhibits antiproliferative and proapoptotic activities in several hematological cell lines. -
KAT5 (Tip60) HAT inhibitor
NU9056 is an selective KAT5 (Tip60) HAT inhibitor. IC50 values are < 2, 60, 36, and >100 μM for KAT5, p300, pCAF and GCN5, respectively. Inhibits protein acetylation in prostate cancer cell lines and blocks DNA damage response. Decreases proliferation of LNCaP cells; induces apoptosis via caspase activation. -
CDK/JAK2/FLT3 inhibitor
SB1317 is a potent inhibitor of Cyclin dependent kinases (CDKs), FMS-like tyrosine kinase-3 (FLT3) and Janus kinase 2 (JAK2) with IC50 values of 13nM, 56nM and 73nM for CDK2, JAK2 and FLT3, respectively. -
JAK inhibitor
JAK Inhibitor I is a potent, reversible, cell-permeable, and ATP-competitive inhibitor of JAK1, JAK2, and JAK3. -
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. -
JAK3 inhibitor
ZM 39923 HCl is an inhibitor of JAK3 (IC50 = 79 nM) that less potently inhibits epidermal growth factor receptor, JAK1, and cyclin-dependent kinase 4 (IC50s = 2.4, 40, and 10 M, respectively) -
Aurora kinase A inhibitor
TC-A-2317 hydrochloride is a potent Aurora kinase A inhibitor (Ki = 1.2 nM compared to 101 nM for inhibition of Aurora kinase B). Selective over 60 other kinases (IC50 values > 1000 nM). Exhibits good cell permeability and antitumor activity.