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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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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FLT3 inhibitor
TG-02 is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. -
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. -
CDK inhibitor
Flavopiridol (Alvocidib) is a cyclin-dependent kinase inhibitor under clinical development for the treatment of chronic lymphocytic leukemia.- Reiko Watanabe, .et al. , J Med Chem, 2021, Mar 11;64(5):2725-2738 PMID: 33619967
- Zhiyuan Zhao, .et al. , J Biol Chem, 2017, Sep 15; 292(37): 15489-15500 PMID: 28743741
- Sami Kukkonen, .et al. , Retrovirology., 2014, 11: 30. PMID: 24742347
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CDK 4/6 inhibitor
PD 0332991 HCl is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity.- Hiroki Ozawa, .et al. , Transl Oncol, 2022, Feb;16:101307 PMID: 34902741
- Cong Li, .et al. , Mol Cancer Ther., 2015, Feb;14(2):375-83. PMID: 25487917
- Pirita Pekkonen, .et al. , Cell Cycle, 2014, Dec 1; 13(23): 3670-3684 PMID: 25483078
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CDK Inhibitor
PHA-793887, a novel potent inhibitor of Cdk, target on kinds of cyclin-dependent kinase under low concentrations and poses high activity against several cancer cell lines.- Hirosumi Tamura, .et al. , Oncol Rep, 2018, Aug; 40(2): 635-646 PMID: 29917168
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CDK Inhibitor
Roscovitine (Seliciclib) is a CDK inhibitor that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9.- Reiko Watanabe, .et al. , J Med Chem, 2021, Mar 11;64(5):2725-2738 PMID: 33619967
- Vimal Pandey, .et al. , Scientific Reports, 2019, 9, Article number: 5012 PMID: 30899038
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CDK inhibitor
SNS-032 (BMS-387032) is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. -
Akt inhibitor
A-674563 is a B/Akt inhibitor with an IC50 of 14 nM and also shows inhibitory activity against PKA and CDK2 with IC50 of 16 and 46 nM, respectively.- Kobayashi T, .et al. , Biochem Biophys Res Commun, 2018, Jan 1;495(1):1468-1475 PMID: 29196261
- Lin Xu, .et al. , Biochem Biophys Res Commun, 2016, Apr 15;472(4):662-8 PMID: 26920060
- Zou Y, .et al. , Biochem Biophys Res Commun, 2016, Aug 12;477(1):1-8 PMID: 26970307
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CDK inhibitor
Flavopiridol HCl is an inhibitor of cyclin-dependent kinases. The (-)-cis form induces apoptosis in particular tumor cells. -
CDK Inhibitor
PHA-848125 (Milciclib) is an orally bioavailable inhibitor of CDKs and TRKA with potential antineoplastic activity. -
CDK Inhibitor
Dinaciclib (SCH 727965) is a potent and selective cyclin-dependent kinase (CDK) inhibitor, selectively inhibiting CDK1, CDK2, CDK5 and CDK9 with IC50 values of 3, 1, 1 and 4 nM respectively.- Vijaya Bharti, .et al. , Cell Rep, 2022, Dec 20;41(12):111826 PMID: 36543138
- Sepideh Izadi, .et al. , Pharm Res, 2020, Sep 17;37(10):196 PMID: 32944844
- Shahin Hallaj, .et al. , Life Sci, 2020, Jul 26 PMID: 32726663
- Washio I, .et al. , Drug Metab Dispos, 2018, Mar;46(3):214-222 PMID: 29246888
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CDK inhibitor
BMS-265246 is a potent new pyra- zolopyridine inhibitor of cdk2/cyclin E and cdk1/cyclin B, as well as cdk4/cyclin D. -
Cdc7/cdk9 inhibitor
PHA-767491 is a potent, ATP-competitive dual cdc7/cdk9 inhibitor (IC50 values are 10 and 34 nM respectively) that prevents initiation of DNA replication.
- Lei Tan, .et al. , Res Vet Sci, 2022, 145: 125-134 PMID: 35190327
- Qi Li, .et al. , Transl Oncol, 2018, Apr; 11(2): 300-306 PMID: 29413763
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Chk1 inhibitor
SCH900776 is an agent targeting cell cycle checkpoint kinase 1 (Chk1) with potential radiosensitization and chemosensitization activities. It specifically binds to and inhibits Chk1, which may result in tumor cells bypassing Chk1-dependent cell cycle arrest in the S and G2/M phases to undergo DNA repair prior to entry into mitosis; tumor cells may thus be sensitized to the DNA-damaging effects of ionizing radiation and alkylating chemotherapeutic agents.
- Hong Yang, .et al. , Research Square, 2022, May 9th
- Motofumi Suzuki, .et al. , Int J Radiat Oncol Biol Phys, 2021, May 25;S0360-3016(21)00361-8 PMID: 34112559
- Min Wu, .et al. , Haematologica, 2019, 104 PMID: 30975911
- Permata TBM, .et al. , Oncogene, 2019, Feb 12 PMID: 30755733
- Hiro Sato, .et al. , Nat Commun, 2017, 8: 1751 PMID: 29170499
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CDK inhibitor
Kenpaullone is a potent inhibitor of CDK1/cyclin B (IC?????€ = 400 nM), CDK2/cyclin A (IC?????€ = 680nM) , CDK5 (IC?????€ = 850nM) and with much less effect other kinases.- Katelyn M Green, .et al. , J Biol Chem, 2019, jbc.RA119.009951
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CDK inhibitor
AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs), which may result in cell cycle arrest, induction of apoptosis, and inhibition of tumor cell proliferation. -
Ca2+ channel agonist/CDK2 inhibitor
Ca2+ channel agonist 1 is an agonist of N-type Ca2+ channel and an inhibitor of Cdk2, with EC50s of 14.23 μM and 3.34 μM, respectively, and is used as a potential treatment for motor nerve terminal dysfunction. -
CDK inhibitor
Purvalanol B is a cyclin-dependent kinase inhibitor. IC50 values are 6, 6, 9, > 10,000, and 6 nM for cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D1 and cdk5-p35 respectively. Selective over a range of other protein kinases (IC50 > 10,000 nM). -
CDK8 inhibitor
MSC2530818 is a potent, selective and orally available CDK8 inhibitor with an IC50 of 2.6 nM for CDK8. -
CDK inhibitor
BAY 1000394 is an orally bioavailable cyclin dependent kinase (CDK) inhibitor with potential antineoplastic activity.- Marzia Ognibene, .et al. , Sci Rep, 2020, 10: 12902 PMID: 32737364
- Xinan (Holly) Yang, .et al. , Sci Rep, 2017, 7: 41 PMID: 28246384
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CDK4/6 inhibitor
LY2835219 is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity.- Elaheh S Abutorabi, .et al. , Mol Biol Rep, 2023, May;50(5):4073-4082 PMID: 36877344
- Yoshinori Tanaka, .et al. , Biochem Biophys Res Commun, 2022, Jul 23;614:191-97 PMID: 35598430
- Sumire Suzuki, .et al. , Oncol Rep, 2022, Feb;47(2):40 PMID: 34958115
- Kana Nakatani, .et al. , Int J Hematol, 2020, Oct 17 PMID: 33068248
- Ryohei Ogata, .et al. , Breast Cancer, 2020, Aug 28 PMID: 32860163
- Elaheh Seyed Abutorabi, .et al. , Rep Biochem Mol Biol, 2020, Jan; 8(4): 438-445 PMID: 32582803
- Hidemasa Matsuo, .et al. , Blood Adv, 2018, Nov 13; 2(21): 2879-2889 PMID: 30381403
- Iriyama N, .et al. , Leuk Lymphoma, 2018, Jun;59(6):1439-1450 PMID: 28918692
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CDK inhibitor
RGB-286638 is a novel CDK inhibitor with IC50s of 1 nM/2 nM/3 nM/4 nM/5 nM for cyclin T1-CDK9/cyclin B1-CDK1/cyclin E-CDK2/cyclin D1-CDK4/cyclin E-CDK3/p35-CDK5 respectively; less potent against cyclin H-CDK7 and cyclin D3-CDK6. -
Cdc25 inhibitor
NSC 663284 is a potent, cell-permeable, and irreversible inhibitor of all Cdc25 isoforms, with preference for Cdc25A (IC50 = 29, 95, and 89 nM for Cdc25A, Cdc25B2, and Cdc25C, respectively). -
CDK4/6 inhibitor
LEE011 is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity.- Federico Antoniciello, .et al. , Front Mol Biosci, 2023, May 11;9:887564 PMID: 35647033
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CDK inhibitor
BMS-863233, also known as XL-413, is an orally bioavailable cell division cycle 7 homolog (CDC7) kinase inhibitor with potential antineoplastic activity.- Gijs Zonderland, .et al. , Mol Cell, 2022, Sep 15;82(18):3350-3365 PMID: 36049481
- Wang C, .et al. , Nature, 2019, Oct 2 PMID: 31578521
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CDK4/6 inhibitor
PD 0332991 Isethionate is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM respectively. -
CDK7 Inhibitor
THZ1 is a novel selective and potent covalent CDK7 inhibitor with IC50(binding affinity) of 3.2 nM; inhibits Jurkat cell's proliferation with IC50 of 50 nM- Guowang Li, .et al. , Life Sci Alliance, 2023, Apr 3;6(6):e202201854 PMID: 37012048