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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JAK Inhibitor
Baricitinib, also known as INCB028050 or LY3009104, is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM).- Lokesh Sharma, .et al. , Physiol Rep, 2025, Feb;13(3):e70232 PMID: 39921246
- Renlei Feng, .et al. , BMC Cardiovasc Disord, 2025, Jan 31;25(1):65 PMID: 39891042
- Hongli Liu, .et al. , Adv Rheumatol, 2023, Aug 28;63(1):45 PMID: 37641106
- Dandan Wang, .et al. , Adv Rheumatol, 2023, May 16;63(1):22 PMID: 37194022
- Yuki Sasaki, .et al. , JCI Insight, 2022, Apr 8;7(7) PMID: 35393946
- Yutian Lei, .et al. , Kidney Int, 2021, Feb 16 PMID: 33607177
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EZH2 inhibitor
GSK126 is a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes.- Lucy E. Dawson, .et al. , Sarcoma, 2020, 2020: 8647981 PMID: 32300280
- Hirosumi Tamura, .et al. , Oncol Rep, 2018, Aug; 40(2): 635-646 PMID: 29917168
- Dupret B, .et al. , Biochim Biophys Acta Gene Regul Mech, 2017, Oct;1860(10):1079-1093 PMID: 28887218
- Theresa Baker, .et al. , Oncotarget, 2015, Oct 20; 6(32): 32646-32655 PMID: 26360609
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PARP1/2 inhibitor
Talazoparib tosylate (BMN 673ts) is a novel, potent and orally available PARP1/2 inhibitor with an IC50 of 0.57 nM for PARP1.- Majid Momeny, .et al. , EMBO Mol Med, 2024, Jun 17 PMID: 38886591
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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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HDAC inhibitor
R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models.- Mari Ishigami-Yuasa, .et al. , Biol Pharm Bull, 2019, 42, 448-452 PMID: 30828077
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HDAC Inhibitor
MGCD0103 (Mocetinostat) is a benzamide histone deacetylase inhibitor by inhibiting mainly histone deacetylase 1 (HDAC1), but also HDAC2, HDAC3, and HDAC11.- Mari Ishigami-Yuasa, .et al. , Biol Pharm Bull, 2019, 42, 448-452 PMID: 30828077
- Guang Bai, .et al. , Epigenetics of Chronic Pain, 2019, Pages 1-48
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EGFR inhibitor
AG 490 is a selective inhibitor of EGF receptor tyrosine kinase (IC50 values are 2 and 13.5 μM for EGFR and ErbB2 respectively). Also inhibits JAK2 with no activity to Lck, Lyn, Btk, Syk and Src.- Matozaki M, .et al. , Exp Cell Res, 2019, Feb 15. pii: S0014-4827(18)31030-9 PMID: 30776355
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JAK1/2 Inhibitor
INCB018424 is a potent and selective inhibitor of Janus-associated kinase (JAK) 1 and 2, with IC50 to be 2.7, 4.5 and 332 nM for JAK1, JAK2 and JAK3 respectively;- Meenu Kesarwani, .et al. , Blood Adv, 2024, Jun 11;8(11):2765-2776 PMID: 38531054
- Aya Hasan Alshammari, .et al. , Biochem Pharmacol, 2022, Mar;197:114914 PMID: 35041812
- Daniel Doheny, .et al. , Oncogene, 2020, Oct;39(42):6589-6605 PMID: 32929154
- Rasmus Siersbek, .et al. , Cancer cell, 2020, Jul 6;S1535-6108(20)30311-1 PMID: 32679107
- Brittany M. Duggan, .et al. , Sci Rep, 2017, 7: 1578 PMID: 28484277
- Fujita KI, .et al. , J Pharm Sci, 2017, Sep;106(9):2632-2641 PMID: 28479358
- Kagoya Y, .et al. , Blood., 2014, Nov 6;124(19):2996-3006 PMID: 25217696
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HDAC inhibitor
JNJ-26481585 (Quisinostat) is a pan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L).- Minoru Ueda, .et al. , Plant Physiol, 2017, Dec; 175(4): 1760-1773 PMID: 29018096
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BET Bromodomain Inhibitor
GSK1210151A is a novel selective inhibitor of the bromodomain and extra terminal (BET) family proteins BRD2, BRD3, and BRD4.- Momeny M, .et al. , Anticancer Drugs, 2018, Nov;29(10):1011-1020 PMID: 30096128
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DNMT inhibitor
Azacitidine is a chemical analogue of the cytosine nucleoside used in DNA and RNA that is mainly used in the treatment of myelodysplastic syndrome (MDS).- Nageswara Rao Reddy, .et al. , Bioanalysis, 2022, Mar;14(5):253-266 PMID: 35172610
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LSD1 inhibitor
GSK2879552 is an orally available, irreversible, inhibitor of lysine specific demethylase 1 (LSD1), with potential antineoplastic activity.- Nicolas A Fraunhoffer, .et al. , EBioMedicine, 2023, Jun;92:104602 PMID: 37148583
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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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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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Pdia3/ERp57 activator, STAT3 inhibitor
Diosgenin is a steroid sapogenin and the precursor for the semisynthesis of progesterone which in turn was used in early combined oral contraceptive pills.It is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro.- Rashmi Rawat, .et al. , Food Chemistry Advances, 2022, 1: 100092
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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
AZ-960 is a potent, selective and ATP competitive JAK2 inhibitor that inhibits JAK2 kinase with a Ki of 0.45 nM in vitro and induces growth arrest and apoptosis in adult T-cell leukemia (ATL) cell.- Rongshou Wu, .et al. , Sci Rep, 2023, 13: 16998 PMID: 37813900
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Aurora Kinase B inhibitor
AZD 1152-HQPA is a highly potent and selective inhibitor of Aurora B, with Ki values to be 0.36 (Aurora B) and 1369 nM (Aurora A) respectively and has a high specificity versus a panel of 50 other kinases.- Sakamoto K, .et al. , Leukemia, 2018, May 23 PMID: 29795241
- Jennifer M. Sahni, .et al. , J Biol Chem, 2016, Nov 4; 291(45): 23756-23768 PMID: 27650498
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HDAC inhibitor
Sulforaphane activates Nrf2 and inhibits high glucose-induced progression of pancreatic cancer via AMPK dependent signaling. Sulforaphane has shown anti-cancer and anti-inflammatory activities.- Satoshi Endo, .et al. , J Biochem, 2021, Mar 17 PMID: 33729485
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HDAC inhibitor
Belinostat (PXD101) is a HDAC inhibitor that inhibits HDAC activity in HeLa cell extracts with an IC50 of 27 nM.- Shariful Islam, .et al. , Blood Adv, 2020, 4(20): 5297-5310 PMID: 33108458
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PARP inhibitor
XAV 939 is a TNKS inhibitor (IC50 values are 0.011 and 0.004 μM for TNKS1 and TNKS2 respectively).- Shizu Aikawa, .et al. , EMBO J, 2017, Jul 14; 36(14): 2146-2160 PMID: 28588064
- Mikaël M. Martino, .et al. , Nat Commun, 2016, 7: 11051 PMID: 27001940
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JAK2 Inhibitor
WP1066 is a novel JAK2 inhibitor and it suppresses proliferation and induces apoptosis in eythroid human cells carrying the JAK2 V617F mutation.- Simona Moravcova, .et al. , Life (Basel), 2021, Oct 18;11(10):1105 PMID: 34685476
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JAK1/JAK2 Inhibitor
AZD1480 is a novel potent small JAK2 inhibitor with an IC50 of 0.26 nM.- Simona Moravcova, .et al. , Life (Basel), 2021, Oct 18;11(10):1105 PMID: 34685476
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HDAC inhibitor
Vorinostat is an inhibitor of HDACs, inhibiting deacetylation and leading to an accumulation of both hyperacetylated histones and transcription factors.- Siva Singothu, .et al. , ACS Infect Dis, 2025, Jul 11;11(7):1922-1933 PMID: 40509567
- Masahiro Yamada, .et al. , Int J Hematol, 2024, Sep;120(3):325-336 PMID: 38954186
- Amy E Neely, .et al. , Commun Biol, 2023, Jun 23;6(1):664 PMID: 37353594
- Ting-Yu Chang, .et al. , Biomed Pharmacother, 2021, Jun;138:111485 PMID: 33740521
- David Diaz-Carballo, .et al. , Commun Biol, 2021, Mar 3;4(1):276 PMID: 33658617
- Arshdeep Singh, .et al. , Eur J Med Chem, 2021, Apr 5;215:113169 PMID: 33588178
- Shariful Islam, .et al. , Blood Adv, 2020, 4(20): 5297-5310 PMID: 33108458
- Giovanni Bocci, .et al. , ACS Pharmacol Transl Sci, 2020, Oct 14
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HDAC Inhibitor
Trichostatin A (TSA) inhibits the HDACs 1, 3, 4, 6 and 10 with IC50 values around 20 nM.- Siva Singothu, .et al. , ACS Infect Dis, 2025, Jul 11;11(7):1922-1933 PMID: 40509567
- Thibaud Reyser, .et al. , Pharmaceutics, 2023, Oct 10;15(10):2440 PMID: 37896200
- Goudreault M, .et al. , Research Square, 2021, 22 Nov
- Hiroyuki Imuta, .et al. , Heart Vessels, 2020, Jul 16 PMID: 32676696
- Méndez-Blanco C, .et al. , Cancers (Basel), 2019, Dec 9;11(12). pii: E1984 PMID: 31835431
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HDAC inhibitor
MS-275 (Entinostat) is a potent HDAC inhibitor with IC50 of 0.3 and 8uM for HDAC1 and HDAC3, respectively.- Siva Singothu, .et al. , ACS Infect Dis, 2025, Jul 11;11(7):1922-1933 PMID: 40509567
- Wenguang Liu, .et al. , Biochem Biophys Res Commun, 2024, Dec 20:739:150970 PMID: 39550862
- Vivek Bora, .et al. , Can J Physiol Pharmacol, 2021, 6 October
- Taito Kashio, .et al. , Tissue Barriers, 2021, May 6;1911195 PMID: 33955828
- Ting-Yu Chang, .et al. , Biomed Pharmacother, 2021, Jun;138:111485 PMID: 33740521
- Arshdeep Singh, .et al. , Eur J Med Chem, 2021, Apr 5;215:113169 PMID: 33588178
- Minoru Ueda, .et al. , Plant Physiol, 2017, Dec; 175(4): 1760-1773 PMID: 29018096
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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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PARP inhibitor
ABT-888(Veliparib) is a potential anti-cancer drug acting as a PARP inhibitor.- Subhajit Chatterjee, .et al. , Cell Signal, 2021, Apr;80:109902 PMID: 33373686
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PARP inhibitor
BMN-673 is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity.- Subhajit Chatterjee, .et al. , J Cancer Res Clin Oncol, 2022, Dec;148(12):3521-3535 PMID: 35962813
- Charles-André Philip, .et al. , BMC Cancer, 2017, 17: 638 PMID: 28886696
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Histone Demethylase inhibitor
JIB-04 is a pan-selective Jumonji histone demethylase inhibitor with IC50 of 230, 340, 855, 445, 435, 1100, and 290 nM for JARID1A, JMJD2E, JMJD3, JMJD2A, JMJD2B, JMJD2C, and JMJD2D, respectively.- Thibaud Reyser, .et al. , Pharmaceutics, 2023, Oct 10;15(10):2440 PMID: 37896200
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KAT5 (Tip60) HAT inhibitor
MG149 is a potent histone acetyltransferase inhibitor with IC50 of 74 uM and 47 uM for Tip60 and MOF.- Thibaud Reyser, .et al. , Pharmaceutics, 2023, Oct 10;15(10):2440 PMID: 37896200
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p300/CBP inhibitor
C646 is a selective p300/CREB-binding protein (CBP) inhibitor (Ki = 400 nM).- Thibaud Reyser, .et al. , Pharmaceutics, 2023, Oct 10;15(10):2440 PMID: 37896200
- Zhifeng Zhang, .et al. , PLoS One, 2017, 12(10): e0186900 PMID: 29049411
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DNA Methyltransferase Inhibitors
Decitabine is a hypomethylating agent.It hypomethylates DNA by inhibiting DNA methyltransferase.- Tianxing Ying, .et al. , Cancers (Basel), 2022, Dec 30;15(1):243 PMID: 36612238
- Borbala Szabo, .et al. , J Clin Endocrinol Metab, 2022, Sep 5;dgac496 PMID: 36059148
- Sangni Qian, .et al. , Clin Epigenetics, 2022, Sep 5;14(1):111 PMID: 36064442
- Borb??la Szab??, .et al. , J Clin Endocrinol Metab, 2020, Jun 1;105(6):dgaa156 PMID: 32232382
- Bracha Shraibman, .et al. , Mol Cell Proteomics, 2016, Sep; 15(9): 3058-3070 PMID: 27412690
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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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PARP inhibitor
PJ34 is a novel potent specific inhibitor of PARP-l/2 with EC50 of 20 nM.- Tim J Wigle, .et al. , Cell Chem Biol, 2020, Jul 16;27(7):877-887 PMID: 32679093
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mTOR inhibitor
FK-506 is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It reduces interleukin-2 (IL-2) production by T-cells.- Tomoya Terashima, .et al. , Regenerative Cellular Therapies for Neurological Diseases, 2025, August: 95-107
- Ogawa Y, .et al. , Neurobiol Dis, 2018, Oct;118:142-154 PMID: 30026035
- Yuko Okamoto, .et al. , J Drug Deliv Sci Technol, 2018, 47: 62-66
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Aurora inhibitor
Danusertib (PHA-739358) is an Aurora kinase inhibitor for Aurora A/B/C with IC50 of 13 nM/79 nM/61 nM in cell-free assays, modestly potent to Abl, TrkA, c-RET and FGFR1, and less potent to Lck, VEGFR2/3, c-Kit, CDK2, etc. Phase 2- Vijaya Bharti, .et al. , Cell Rep, 2022, Dec 20;41(12):111826 PMID: 36543138
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Chk2, KDR, FGFR, Aurora A & Cdk2 inhibitor
R1530 is a pyrazolobenzodiazepine small molecule with potential antiangiogenesis and antineoplastic activities. R1530 is also a mitosis-angiogenesis inhibitor (MAI) that inhibits multiple receptor tyrosine kinases involved in angiogenesis, such as vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, platelet-derived growth factor receptor (PDGFR) beta? FMS-like tyrosine kinase (Flt)-3, and fibroblast growth factor receptor (FGFR) -1, -2.- Vijaya Bharti, .et al. , Cell Rep, 2022, Dec 20;41(12):111826 PMID: 36543138
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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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PARP1 inhibitor
AG14361 is a potent PARP inhibitor, enhanced TMZ cytotoxicity in MMR(mismatch repair)-proficient / deficient cells.- Vimal Pandey, .et al. , Scientific Reports, 2019, 9, Article number: 5012 PMID: 30899038
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Aurora A Kinase inhibitor
MK-5108, also known as VX-689, is a competitive inhibitor of the ATP-binding site of aurora A kinase.- Wei TW, .et al. , Cancer Res, 2017, Jan 15;77(2):494-508 PMID: 28069801
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Aurora B Kinase inhibitor
Hesperadin is a human Aurora B inhibitor with an IC50 of 40 nM for the prevention of the phosphorylation of substrate. It markedly reduces the activity of AMPK, Lck, MKK1, MAPKAP-K1, CHK1 and PHK while it does not inhibit MKK1 activity in vivo.- Wenbin Ji, .et al. , PLoS One, 2016, 11(4): e0153518 PMID: 27082996
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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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JAK inhibitor
JAK Inhibitor I is a potent, reversible, cell-permeable, and ATP-competitive inhibitor of JAK1, JAK2, and JAK3.- Ya-Ge Zhang, .et al. , J Neuroinflammation, 2023, Sep 27;20(1):216 PMID: 37752509
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Selective SIRT2 inhibitor
SirReal2 is a potent and selective Sirt2 inhibitor with IC50 of 140 nM.- Yang Li, .et al. , Neoplasia, 2018, Jul; 20(7): 745-756 PMID: 29925042
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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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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

