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 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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IGF-1R, Aurora, FGFR, ABL, SRC inhibitor
XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1-3, ABL and SRC family kinases. XL228 is an Aurora A inhibitor (IC50, f3 nmol/L) that has shown potent biochemical activity against ABL1 (Ki, 5 nmol/L), as well as the BCR-ABL1 T315I (Ki, 1.4 nmol/L) kinases. -
BCR-ABL inhibitor
AP24534 (Ponatinib) is a potent multi-kinase and pan-BCR-ABL inhibitor.- Aya Hasan Alshammari, .et al. , Biochem Pharmacol, 2022, Mar;197:114914 PMID: 35041812
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- Fujita KI, .et al. , J Pharm Sci, 2017, Sep;106(9):2632-2641 PMID: 28479358
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Src/Abl inhibitor
Saracatinib (AZD0530) is a highly selective, orally available, dual-specific Src/Abl kinase inhibitor with IC50 of 2.7 and 30 nM for c-Src and Abl kinase, respectively.- Andromachi Lambrianidou, .et al. , Cell Signal, 2021, Apr;80:109912 PMID: 33388443
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Bcr-Abl inhibitor
Bafetinib ((INNO-406) is a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia.- Yusuke Kimata, .et al. , Life Sci Alliance, 2023, Feb 27;6(5):e202201657 PMID: 36849250
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PDGFR inhibitor
Imatinib (Gleevec) is a number of tyrosine kinase enzymes specific inhibitor.- Aya Hasan Alshammari, .et al. , Biochem Pharmacol, 2022, Mar;197:114914 PMID: 35041812
- Takafumi Shima, .et al. , Oncol Rep, 2022, 47: 7 PMID: 34738628
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- Li Li, .et al. , Leukemia Res, 2019, 78:12-20 PMID: 30660961
- Brittany M. Duggan, .et al. , Sci Rep, 2017, 7: 1578 PMID: 28484277
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Abl-Src inhibitor
Dasatinib (BMS-354825) is an oral multi- BCR/ABL and Src family tyrosine kinase inhibitor. The main targets of dasatinib, are BCR/ABL, Src, c-Kit, ephrin receptors, and several other tyrosine kinases, but not erbB kinases such as EGFR or Her2.- Hiroto Kataoka, .et al. , Anal Biochem, 2023, Oct 1;678 PMID: 37541642
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- Aya Hasan Alshammari, .et al. , Biochem Pharmacol, 2022, Mar;197:114914 PMID: 35041812
- Adi Jacob Berger, .et al. , Nat Cancer, 2021, 2, 1055-1070 PMID: 35121883
- David E J Klawon, .et al. , J Exp Med, 2021, Jun 7;218(6) PMID: 33914024
- Reiko Watanabe, .et al. , J Med Chem, 2021, Mar 11;64(5):2725-2738 PMID: 33619967
- Li Li, .et al. , Leukemia Res, 2019, 78:12-20 PMID: 30660961
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- John D. Leonard, .et al. , Immunity, 2017, Jul 18; 47(1): 107-117.e8 PMID: 28709804
- Fujita KI, .et al. , J Pharm Sci, 2017, Sep;106(9):2632-2641 PMID: 28479358
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Bcr-Abl inhibitor
Imatinib mesylate, a selective tyrosine kinase inhibitor, induced a sustained objective response in treating gastrointestinal stromal tumors with the inhibition of the KIT signal-transduction pathway.- Inge Govaerts, .et al. , J Hematol Oncol, 2021, 14: 97 PMID: 34167562
- Genevra Kuziel, .et al. , Cancers (Basel), 2020, Jul 28;12(8):E2083 PMID: 32731354
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Bcr-Abl inhibitor
Nilotinib is a Bcr-Abl inhibitor with IC50 less than 30 nM.- Rami Shinnawi, .et al. , Stem Cell Reports, 2015, Oct 13; 5(4): 582-596 PMID: 26372632
- Tetsuya Saita, .et al. , Biol Pharm Bull. , 2015, 38(10):1652-7 PMID: 26424026
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EphB4 inhibitor
NVP-BHG712 is a selective inhibitor of EphB4 kinase that exhibits selectivity for EphB4 over more than 40 other kinases in vitro, including FGFR3.- Y Kaibori, .et al. , the FASEB Journal, 2019, Jan 22:fj201801519RR PMID: 30668924
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DUB/Bcr/ABL Inhibitor
WP1130 (Degrasyn) is a novel selective small molecular deubiquitinase inhibitor and a Bcr/Abl destruction pathway activator that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells.- Kevin Bohm, .et al. , Arch Pharm (Weinheim), 2023, Jul;356(7):e2200661 PMID: 37196427
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Bcr-Abl inhibitor
DCC-2036 is an orally bioavailable small-molecule inhibitor of multiple tyrosine kinases with potential antineoplastic activity.
- Hirosumi Tamura, .et al. , Oncol Rep, 2018, Aug; 40(2): 635-646 PMID: 29917168
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Bcr-Abl inhibitor
Nilotinib is a Bcr-Abl inhibitor with IC50 less than 30 nM. -
Bcr-Abl Inhibitor
GZD824 is a novel orally bioavailable Bcr-Abl inhibitor for Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 of 0.34 nM and 0.68 nM, respectively. -
multi-kinase inhibitor
Flumatinib is a multi-kinase inhibitor with IC50 Values of 1.2 nM, 307.6 nM and 2662 nM for c-Abl, PDGFRbeta and c-Kit respectively. -
Bcr-Abl inhibitor
GZD824 is a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. -
Src/c-Abl inhibitor
1-Naphthyl PP1 hydrochloride is a selective inhibitor of src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl (IC50 values are 1.0, 0.6, 0.6, 18 and 22 μM for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively). -
Bcr-Abl1 inhibitor
Vodobatinib, also known as K-0706, is a novel 3rd generation (3G) TKI effective against wild-type and mutated BCR-ABL1 with limited off-target activity.