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 inhibitor
Remetinostat (SHP-141) is a hydroxamic acid-based inhibitor of histone deacetylase enzymes (HDAC) which is under development for the treatment of cutaneous T-cell lymphoma. -
KDM4A inhibitor
Toxoflavin (Xanthothricin) is an antagonist of transcription factor 4 (TCF4)/β-catenin complex, also acts as an inhibitor of KDM4A, with antitumor activity. -
G9a inhibitor
CPUY074020 is a potent G9a inhibitor with an IC50 of 2.18 μM, and possesses anti-proliferative activity . -
PAD inhibitor
Cl-amidine is a peptidylarginine deminase (PAD) inhibitor, with an IC50 5.9 μM for PAD4. -
miR-544 inhibitor
SID 3712249 (MiR-544 Inhibitor 1) is an inhibitor of the biogenesis of microRNA-544 (miR-544). -
p53 activator
Tenovin-6 is a analog of tenovin-1. Tenovin-6 inhibits the protein deacetylase activities of purified human SIRT1, SIRT2, and SIRT3 in vitro with IC50 values of 21, 10, and 67 uM, respectively.- Igase M,, .et al. , Exp Cell Res, 2019, Dec 28:111810 PMID: 31891684
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p300 inhibitor
Histone Acetyltransferase Inhibitor II is a potent and cell permeable p300 inhibitor, with an IC50 of 5μM; Histone Acetyltransferase Inhibitor II can be used in cancer research. -
BET inhibitor
PFI-1 is a BET bromodomain inhibitor that exhibits inhibitory activity at BRD2 and BRD4.- Lisa-Maria Winter, .et al. , Sci Rep, 2023, Jul 26;13(1):12061 PMID: 37495707
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Dot1L inhibitor
Dot1L-IN-1 is a highly potent, selective and structurally novel Dot1L inhibitor with a Ki of 2 pM. -
HDAC inhibitor
Resminostat, also known as RAS2410, is a potent inhibitor of histone deacetylase (HDAC) classes I and II. It binds to and inhibits HDACs leading to an accumulation of highly acetylated histones. -
pan-JAK inhibitor
PF-06263276 (PF 6263276) is a potent and selective pan-JAK inhibitor, with IC50s of 2.2 nM, 23.1 nM, 59.9 nM and 29.7 nM for JAK1, JAK2, JAK3 and TYK2, respectively. -
HDAC4 inhibitor
Tasquinimod is an orally active antiangiogenic agent by allosterically inhibiting HDAC4 signalling. -
PARP inhibitor
PJ 34 hydrochloride is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) (EC50 = 20 nM).- Wigle TJ, .et al. , SLAS Discov, 2019, Dec 19:2472555219883623 PMID: 31855104
- Alvin Z.Lu, .et al. , Biochem Pharmacol, 2019, May 7. pii: S0006-2952(19)30171-6 PMID: 31075269
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JAK2/FLT3 inhibitor
Pacritinib, also known as SB1518, is an orally bioavailable inhibitor of Janus kinase 2 (JAK2) and the JAK2 mutant JAK2V617F with potential antineoplastic activity. Pacritinib competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis.- Daniel Doheny, .et al. , Oncogene, 2020, Oct;39(42):6589-6605 PMID: 32929154
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EZH2 inhibitor
EPZ-6438 is a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity. It induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells.- Yang PM, .et al. , Am J Cancer Res, 2019, Oct 1;9(10):2120-2139 PMID: 31720078
- Wang Z, .et al. , J Cell Mol Med, 2019, May 13 PMID: 31087496
- Theresa Baker, .et al. , Oncotarget, 2015, Oct 20; 6(32): 32646-32655 PMID: 26360609
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DNA methyltransferase inhibitor
Zebularine (NSC309132; 4-Deoxyuridine) is a DNA methyltransferase inhibitor. -
BET Inhibitor
(+)-JQ1 is a potent, high affinity, selective BET bromodomain inhibitor.- Adriana K Alexander, .et al. , Nat Commun, 2023, Mar 29;14(1):1753 PMID: 36990976
- Haruki Kitamura, .et al. , Biochem Biophys Res Commun, 2023, Jan 22;641:139-147 PMID: 36527748
- Gerald Thiel, .et al. , Pharmaceuticals (Basel), 2022, Jul 10;15(7):846 PMID: 35890145
- Selase D Deletsu, .et al. , Biochem Biophys Res Commun, 2021, Aug 27;567:106-111 PMID: 34146904
- Cole Schonhofer, .et al. , Biochem Pharmacol, 2021, Apr;186:114462 PMID: 33577894
- Nandini Verma, .et al. , Sci Adv, 2020, 6 : eaba8968
- Kuo MT, .et al. , Transl Oncol, 2020, 13(2):355-364 PMID: 31887630
- Rao Z, .et al. , J Immunol, 2019, Aug 15;203(4):1031-1043 PMID: 31300512
- A Carrer, .et al. , Cancer Discov, 2019, Jan 9. pii: CD-18-0567 PMID: 30626590
- Clocchiatti A, .et al. , J Clin Invest, 2018, Dec 3;128(12):5531-5548 PMID: 30395538
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Demethylase Inhibitor
GSK J4 is a cell permeable prodrug rapidly hydrolyzed by macrophage esterases to GSK-J1, a potent selective jumonji H3K27 demethylase inhibitor; attenuates lipopolysaccharide (LPS)-induced proinflammatory cytokine production in primary human macrophages (IC50 = 9 uM for the inhibition of TNF?? release).- Guang Bai, .et al. , Epigenetics of Chronic Pain, 2019, Pages 1-48
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DOT1L Inhibitor
EPZ-5676 is a small molecule inhibitor of histone methyltransferase with potential antineoplastic activity.- Yoo H, .et al. , Cell Death Dis, 2020, Jan; 11(1): 14 PMID: 31908356
- Guang Bai, .et al. , Epigenetics of Chronic Pain, 2019, Pages 1-48
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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