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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BRD4 inhibitor
JQ-1 carboxylic acid is a highly potent, selective and cell-permeable BRD4 inhibitor with IC50s of 77 nM and 33 nM for BRD4(1) and BRD4(2), respectively.- Rahel Fitzel, .et al. , Neoplasia, 2023, Jul;41:100902 PMID: 37148657
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BRD inhibitor
L-45 is the first potent, selective, and cell-active p300/CBP-associated factor (PCAF) bromodomain (Brd) inhibitor with a Kd of 126±15 nM. -
SHP2 inhibitor
SHP099 is a potent, selective, orally available SHP2 inhibitor with an IC50 of 70 nM.- Majid Momeny, .et al. , EMBO Mol Med, 2024, Jun 17 PMID: 38886591
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BET bromodomain inhibitor
PROTAC BET-binding moiety 2 is an inhibitor of BET bromodomain. -
PTP1B/IKK-βinhibitor and dual PPARα and PPARβ agonist
Ertiprotafib is an inhibitor of PTP1B, IkB kinase β (IKK-β), and a dual PPARα and PPARβ agonist, with an IC50 of 1.6 μM for PTP1B, 400 nM for IKK-β, an EC50 of ~1 μM for PPARα/PPARβ. -
miR-210 inhibitor
Targapremir-210 is a potent miR-210 inhibitor with an IC50 of 200 nM in MDA-MB-231 cells. Targapremir-210 binds to the Dicer site of the miR-210 hairpin precursor. This interaction inhibits production of the mature miRNA. -
MicroRNA Inhibitor
MIR96-IN-1 is a selective inhibitor of the biogenesis of microRNA-96. It acts by upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. -
HDAC inhibitor
CG-200745 is a potent HDAC inhibitor which has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. -
ATP-competitive multitargeted kinase inhibitor
Ilorasertib (ABT-348) is a potent and ATP-competitive multitargeted kinase inhibitor, which inhibits Aurora C, Aurora B, and Aurora A with IC50s of 1 nM, 7 nM, 120 nM, respectively. -
HDAC1 inhibitor
Domatinostat tosylate (4SC-202) is a selective class I HDAC inhibitor with IC50 of 1.20 μM, 1.12 μM, and 0.57 μM for HDAC1, HDAC2, and HDAC3, respectively. It also displays inhibitory activity against Lysine specific demethylase 1 (LSD1). -
HDAC inhibitor
Givinostat (ITF-2357) is a HDAC inhibitor with an IC50 of 198 and 157 nM for HDAC1 and HDAC3, respectively. -
PTP1B inhibitor
PTP1B-IN-3 is a potent and selective PTP1B inhibitor with IC50s of 120 nM (PTP1B) and 120 nM (TCPTP), respectively. -
PARP inhibitor
Veliparib dihydrochloride is a potent PARP inhibitor, inhibiting PARP1 and PARP2 with Kis of 5.2 and 2.9 nM, respectively. -
EZH2 inhibitor
PF-06821497 (compound 23a) is a potent, selective and orally active Enhancer of Zeste Homolog 2 (EZH2) inhibitor, with a Ki value <0.1 nM against mutant Y641N EZH2. Exhibits robust tumor growth inhibition. -
EZH1/2 dual inhibitor
Valemetostat tosylate (DS-3201 tosylate) is a first-in-class EZH1/2 dual inhibitor, used in the research of relapsed/refractory peripheral T-cell lymphoma. -
JAK2 inhibitor
NVP-BSK805 dihydrochloride (BSK805 dihydrochloride) is an ATP-competitive JAK2 inhibitor, with IC50s of 0.48 nM, 31.63 nM, 18.68 nM, and 10.76 nM for JAK2 JH1 (JAK homology 1), JAK1 JH1, JAK3 JH1, and TYK2 JH1, respectively. -
Pim inhibitor
INCB053914 phosphate is an inhibitor of Pim extracted from patent WO 2017044730 A1, compound 1; has an IC50 of less than 35 nM. -
HDAC inhibitor
Givinostat hydrochloride (ITF-2357 hydrochloride) is a HDAC inhibitor with an IC50 of 198 and 157 nM for HDAC1 and HDAC3, respectively. -
PARP1/PARP2 inhibitor
E7449 is a potent PARP1 and PARP2 inhibitor and also inhibits TNKS1 and TNKS2, with IC50s of 2.0, 1.0, ?50 and ?50 nM for PARP1, PARP2, TNKS1 and TNKS2, respectively, using 32P-NAD+ as substrate. -
multi-targeted kinase inhibitor
ENMD-2076 Tartrate is a multi-targeted kinase inhibitor with IC50s of 1.86, 14, 58.2, 15.9, 92.7, 70.8, 56.4 nM for Aurora A, Flt3, KDR/VEGFR2, Flt4/VEGFR3, FGFR1, FGFR2, Src, PDGFRα, respectively. -
BET binding to histones inhibitor
(R)-BAY1238097 is the R-isomer with lower activity of BAY1238097. BAY1238097 is a potent and selective inhibitor of BET binding to histones and has strong anti-proliferative activity in different AML (acute myeloid leukemia) and MM (multiple myeloma) models through down-regulation of c-Myc levels and its downstream transcriptome. -
BET inhibitor
(Rac)-BAY1238097 is a BET inhibitor, with an IC50 of 1.02 μM for BRD4. Used in cancer research.

