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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Aurora A Kinase inhibitor
MLN8237 (Alisertib) is a selective Aurora A inhibitor with IC50 of 1.2 nM in a cell-free assay. It has >200-fold higher selectivity for Aurora A than Aurora B. Phase 3..- Shiang-Jie Yang, .et al. , Cell Death Dis, 2024, Jan 30;15(1):103 PMID: 38291041
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Antioxidant, antiangiogenic, antitumor agent
(-)-Epigallocatechin gallate is a potent anti-oxidant polyphenol flavonoid isolated from green tea.- Grace Northrop, .et al. , Food Funct, 2022, Apr 4;13(7):3894-3904 PMID: 35285840
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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
AG-014699 (Rucaparib) is a PARP inhibitor that inhibits poly(ADP-ribose) polymerase (PARP) is a key enzyme in DNA repair.- Ali Divan, .et al. , Pharmacol Res Perspect, 2020, Apr; 8(2): e00586 PMID: 32342655
- Tahira Baloch, .et al. , BMC Cancer, 2019, Jan 10;19(1):44 PMID: 30630446
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PARP 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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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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Aurora A Inhibitor
Aurora A Inhibitor I is a potent and selective inhibitor of Aurora A kinase (AurA), with IC50 values to be 3.4 nM (Aurora A) and unusually high selectivity 1000 fold against Aurora B; a useful tool compound for investigating the cellular role of Aurora A kinases.
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JAK2inhibitor
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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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). -
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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JAK 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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PARP inhibitor
Olaparib (AZD2281) is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.- Saptarshi Sinha, .et al. , Med Oncol, 2024, Jan 6;41(2):49 PMID: 38184505
- Callum G Jones, .et al. , Cancers (Basel), 2024, Feb 21;16(5):863 PMID: 38473223
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- Subhajit Chatterjee, .et al. , J Cancer Res Clin Oncol, 2022, Dec;148(12):3521-3535 PMID: 35962813
- Yuki Uchihara, .et al. , Mol Cell, 2022, Jul 21;82(14):2557-2570 PMID: 35594857
- Ji-Ye Kim, .et al. , Cell Death Dis, 2022, Mar 15;13(3):239 PMID: 35293383
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- Sefinew Molla, .et al. , DNA Repair (Amst), 2021, Jun 10;105:103157 PMID: 34144488
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- Ali Divan, .et al. , Pharmacol Res Perspect, 2020, Apr; 8(2): e00586 PMID: 32342655
- Jianwei Dou, .et al. , J Sep Sci, 2020, Dec 4 PMID: 33275824
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- Chao Zhang, .et al. , J Atheroscler Thromb, 2020, Sep 25 PMID: 32981917
- Wigle TJ, .et al. , SLAS Discov, 2019, Dec 19:2472555219883623 PMID: 31855104
- Wang Q, .et al. , Cancer Med, 2019, Dec 21 PMID: 31863638
- Molla S, .et al. , Pathol Oncol Res, 2019, Nov 25 PMID: 31768967
- Alvin Z.Lu, .et al. , Biochem Pharmacol, 2019, May 7. pii: S0006-2952(19)30171-6 PMID: 31075269
- Bian C, .et al. , Nat Commun, 2019, Feb 11;10(1):693 PMID: 30741937
- HC de Silva, .et al. , Cell Mol Life Sci, 2019, 1-16 PMID: 30725116
- Kamada Y, .et al. , Fitoterapia, 2018, Sep;129:94-101 PMID: 29928967
- 2018, .et al. , FEBS Open Bio, 2018, Jun; 8(6): 1001-1012 PMID: 29928579
- Hirosumi Tamura, .et al. , Oncol Rep, 2018, Aug; 40(2): 635-646 PMID: 29917168
- Hiro Sato, .et al. , Nat Commun, 2017, 8: 1751 PMID: 29170499
- Charles-André Philip, .et al. , BMC Cancer, 2017, 17: 638 PMID: 28886696
- Rulina AV, .et al. , Cell Death Dis, 2016, Dec 1;7(12):e2505 PMID: 27906189
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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
BSI-201 is a potent inhibitor of PARP-1 and has been shown to cross the blood-brain barrier.- Jianwei Dou, .et al. , J Sep Sci, 2020, Dec 4 PMID: 33275824
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Topoisomerase I inhibitor
Camptothecin is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I (topo I).- Kengo Takeda, .et al. , Int J Mol Sci, 2024, Mar 26;25(7):3693 PMID: 38612503
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Aurora Inhibitor
CCT129202 is a representative of a structurally novel series of imidazopyridine small-molecule inhibitors of Aurora kinase activity. It shows high selectivity for the Aurora kinases over a panel of other kinases tested and inhibits proliferation in multiple cultured human tumor cell lines.
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JAK3 inhibitor
CP-690550 (Tofacitinib citrate) is an orally available, highly selective inhibitor of the Janus kinase (JAK) family of enzymes.- Fujita KI, .et al. , J Pharm Sci, 2017, Sep;106(9):2632-2641 PMID: 28479358
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JAK inhibitor
CYT387 is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively.- Bopei Cui, .et al. , Signal Transduct Target Ther, 2023, Sep 25;8(1):366 PMID: 37743418
- Alex Bainbridge, .et al. , Nucleic Acids Research, 2020, April
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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
- Borbála Szabó, .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 gg
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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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HDAC inhibitor
Droxinostat is a selective inhibitor of HDAC3, HDAC6, and HDAC8 that shows comparable inhibition of HDAC6 and HDAC8 with IC50 = 2.47 and 1.46 μmol/L, respectively. -
SIRT1 inhibitor
EX 527 is a potent and selective SIRT1 class III histone deacetylase enzyme inhibitor with IC50 of 38 nM in a cell-free assay.- Qiang Chen, .et al. , J Bioenerg Biomembr, 2022, Feb;55(1):33-42 PMID: 36525212
- Flavien Bizot, .et al. , Mol Ther Nucleic Acids, 2022, Nov 21;30:606-620 PMID: 36514350
- Takeshi Nakamura, .et al. , Shimane Journal of Medical Science, 2022, 38 (2), 59-66
- Bugga Paramesha, .et al. , Antioxidants (Basel), 2021, Feb 24;10(3):338 PMID: 33668369
- Wenhui Yao, .et al. , J Cell Physiol, 2020, 07 August
- Guang Bai, .et al. , Epigenetics of Chronic Pain, 2019, Pages 1-48
- Yoshikawa A, .et al. , J Neurochem, 2015, Feb;132(3):342-53 PMID: 25351847
- Fisetin is a flavonol, a structurally distinct chemical substance that belongs to the flavonoid group of polyphenols. It can be found in many plants, where it serves as a colouring agent. Possible anti-aging, anti-inflammatory, anti-cancer, and anti-viral properties of fisetin are under active scientific investigation.
- Bih-Cheng Chen, .et al. , Phytomedicine, 2019, Apr; 57:1-8
- Jeng LB, .et al. , J Cell Physiol, 2018, Sep;233(9):7134-7142 PMID: 29574877
- Kuan-Ho Lin, .et al. , Journal of Functional Foods, 2018, 52: 212-218
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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.- 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 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
3-Aminobenzamide is a novel PARP inhibitor, known to sensitize cells to radiation in vitro by inhibiting the repair of DNA damage.- Kamada Y, .et al. , Fitoterapia, 2018, Sep;129:94-101 PMID: 29928967
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HDAC inhibitor
ITF2357 (Givinostat) is a HDACs inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.- Flavien Bizot, .et al. , Mol Ther Nucleic Acids, 2022, Nov 21;30:606-620 PMID: 36514350
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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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CDK/Aurora A/B Inhibitor
JNJ-7706621 is pan-CDK inhibitor with the highest potency on CDK1/2 with IC50 of 9 nM/4 nM and showing >6-fold selectivity for CDK1/2 than CDK3/4/6 in cell-free assays. It also potently inhibits Aurora A/B and has no activity on Plk1 and Wee1.- Yuta Tanizaki, .et al. , Commun Biol, 2022, 5: 112 PMID: 35132135
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HDAC Inhibitor
LAQ824 (NVP-LAQ824) is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma.- De-Run Chen, .et al. , Appl Mater Today, 2022, 26: 101363
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HDAC Inhibitor
LBH589 is a hydroxamic acid and acts as a non-selective HDAC inhibitor with IC5o of HDAC1 to be 0.23 nM.- Jalila Chagraoui, .et al. , Cell Stem Cell, 2021, Jan 7;28(1):48-62.e6 PMID: 33417871
- Gils Jose, .et al. , Cancers (Basel), 2020, Oct 31;12(11):E3211 PMID: 33142721
- Shariful Islam, .et al. , Blood Adv, 2020, 4(20): 5297-5310 PMID: 33108458
- Giovanni Bocci, .et al. , ACS Pharmacol Transl Sci, 2020, Oct 14
- Justin Kale, .et al. , EMBO Rep, 2018, Sep; 19(9): e45235 PMID: 29987135
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JAK inhibitor
LY2784544 is identified as being highly selective for JAK2-V617F and has advanced into human clinical trials for the treatment of several myeloproliferative disorders. -
HDAC Inhibitor
MC1568 is a member of HDAC inhibitors that inhibits the histone deacetylase class II by modifying the genetic expression of various important genes of cell cycle mostly at G1 phase, resulting in the death of breast cancer cells by apoptosis.- Bopei Cui, .et al. , Signal Transduct Target Ther, 2023, Sep 25;8(1):366 PMID: 37743418
- Vivek Bora, .et al. , Can J Physiol Pharmacol, 2021, 6 October
- Minoru Ueda, .et al. , Plant Physiol, 2017, Dec; 175(4): 1760-1773 PMID: 29018096
- S Ishikawa, .et al. , Int J Cancer., 2014, 135(11): 2528-2536 PMID: 24346863
- Usui T, .et al. , Hypertension., 2014, Feb;63(2):397-403 PMID: 24166750
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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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HDAC inhibitor
MS-275 (Entinostat) is a potent HDAC inhibitor with IC50 of 0.3 and 8uM for HDAC1 and HDAC3, respectively.- 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
- Parthenolide ((-)-Parthenolide) is a sesquiterpene lactone which occurs naturally in the plant feverfew (Tanacetum parthenium).
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HDAC Inhibitor
PCI-24781 is a broad-spectrum phenyl hydroxamic acid HDAC inhibitor.- Kazuya Tsumagari, .et al. , Biochem Biophys Res Commun, 2021, Jul 23;563:60-65 PMID: 34062387
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Aurora inhibitor
PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3. -
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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HDAC Inhibitor
Pyroxamide (NSC 696085) is a potent inhibitor of affinity-purified HDAC1 and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. -
HDAC inhibitor
SB939 is an oral inhibitor of HDAC, selective for class I, II and IV HDACs and displays an IC50 value of 77 nM in an in vitro HDAC1 activity assay.- Giovanni Bocci, .et al. , ACS Pharmacol Transl Sci, 2020, Oct 14
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PIM1 Inhibitor
SGI-1776 free base is a novel ATP competitive inhibitor of Pim1 with IC50 of 7 nM in a cell-free assay, 50- and 10-fold selective versus Pim2 and Pim3, also potent to Flt3 and haspin. Phase 1.- Ishikawa C, .et al. , Eur J Haematol, 2017, Dec;99(6):495-504 PMID: 28833639