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 inhibitor
Voruciclib is a flavone and cyclin dependent kinase (CDK) inhibitor with potential antineoplastic activity. -
CDK inhibitor
Palbociclib is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity.- Kana Nakatani, .et al. , Int J Hematol, 2020, Oct 17 PMID: 33068248
- Ryohei Ogata, .et al. , Breast Cancer, 2020, Aug 28 PMID: 32860163
- Kishino E, .et al. , Breast Cancer, 2019, Dec 10 PMID: 31823286
- Hidemasa Matsuo, .et al. , Blood Adv, 2018, Nov 13; 2(21): 2879-2889 PMID: 30381403
- Zhihong Li, .et al. , J Med Chem, 2014, Apr 24;57(8):3430-49 PMID: 24641103
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CDK1 inhibitor
Ro 3306 is an ATP-competitive, potent cyclin-dependent kinase (cdk) 1 inhibitor (Ki values are 35 and 110 nM for cdk1/cyclin B1 and cdk1/cyclin A respectively).- Jianming Wang, .et al. , STAR Protoc, 2021, May 29;2(2):100570 PMID: 34136835
- Jianming Wang, .et al. , Cell Rep, 2021, Feb 16;34(7):108759 PMID: 33596418
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CDK inhibitor
AT7519 trifluoroacetate is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM, less potent to CDK3 and little active to CDK7. -
CDK9 inhibitor
CDK9-IN-2 is a novel cyclin-dependent kinase 9(CDK9) inhibitor. -
CDK inhibitor
NVP-LCQ195 is a small molecule heterocyclic inhibitor of CDK1, CDK2, CDK3 and CDK5 with IC50 of 1-42 nM. -
CDK inhibitor
Purvalanol A is a potent, cell-permeable cyclin-dependent protein kinase (cdk) inhibitor. IC50 values are 4, 70, 35, 850 and 75 nM for cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D1 and cdk5-p35 respectively. -
CDC7 inhibitor
LY-3177833 is a potent and selective inhibitor of CDC7 (Cell Division Cycle 7-related Protein Kinase). -
CDK4/6 inhibitor
LY2835219 is a potent and selective inhibitor of CDK4 and CDK6 with IC50 of 2 nM and 10 nM in cell-free assays, respectively. Phase 3.- Shuso Takeda, .et al. , Fundam Toxicol Sci, 2021, 8(3):75-80
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Selective PTEFb/CDK9 inhibitor
Atuveciclib, also known as BAY1143572, is a highly selective, potent and orally available inhibitor of PTEFb/CDK9 currently in Phase I.- Cole Schonhofer, .et al. , Biochem Pharmacol, 2021, Apr;186:114462 PMID: 33577894
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CDK inhibitor
PF-06873600 is an orally bioavailable, cyclin-dependent kinase (CDK) inhibitor, with potential antineoplastic activity.- Abeer J Al-Qasem, .et al. , NPJ Precis Oncol, 2022, Sep 24;6(1):68 PMID: 36153348
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CDK7 inhibitor
ICEC0942, also known as CT7001, is an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. -
CDK4/6 inhibitor
Trilaciclib is a potential first-in-class short-acting CDK4/6 inhibitor in development to preserve hematopoietic stem cells and enhance immune system function during chemotherapy. -
CDK8 inhibitor
SEL120-34A is a potent and selective CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains. -
CDK inhibitor
Lerociclib (G1T38) is a potent and selective inhibitor of CDK4/6, with IC50s of 1 nM, 2 nM for CDK4/CyclinD1 and CDK6/CyclinD3, respectively. -
CDK4/CDK6 inhibitor
Abemaciclib Metabolites M2 is a metabolite of abemaciclib, acts as a potent CDK4 and CDK6 inhibitor, with IC50s in the range of 1-3 nM. Anti-cancer activity. -
CDK4/CDK6 inhibitor
CDK4/6-IN-2 is a potent CDK4 and CDK6 inhibitor with IC50s of 2.7 and 16 nM for CDK4 and CDK6, respectively. -
CDK14 inhibitor
FMF-04-159-2 is a covalent CDK14 inhibitor. FMF-04-159-2 inhibits CDK14 and CDK2 with IC50s of 39.6 nM and 256 nM in NanoBRET assay, respectively. -
CDK9 degrader PROTAC
THAL-SNS-032 is a selective CDK9 degrader PROTAC consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). -
XBP1 inhibitor
Toyocamycin (Vengicide) is an adenosine analog produced by Actinomycete, acts as an XBP1 inhibitor, inhibits IRE1α-induced ATP-dependent XBP1 mRNA cleavage, with an IC50 of 80 nM. -
CDK inhibitor
Indirubin-5-sulfonate is a cyclin-dependent kinase (CDK) inhibitor, with IC50 values of 55 nM, 35 nM, 150 nM, 300 nM and 65 nM for CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK4/cyclin D1, and CDK5/p35, respectively. -
CDK1, CDK5, and GSK-3βinhibitor
Indirubin-3'-monoxime-5-sulphonic acid is a potent and selective inhibitor of CDK1, CDK5, and GSK-3β with IC50s of 5 nM, 7 nM, and 80 nM, respectively. -
GSK-3β, CDK5/P25 and CDK1/cyclin B inhibitor
5-Iodo-indirubin-3'-monoxime is a potent GSK-3β, CDK5/P25 and CDK1/cyclin B inhibitor, competing with ATP for binding to the catalytic site of the kinase, with IC50s of 9, 20 and 25 nM, respectively. -
CDK8 degrader
JH-XI-10-02 is a potent and selective degrader of CDK8, with an IC50 of 159 nM, based on PROTAC. -
CDK4/6 inhibitor
CDK4/6/1 Inhibitor is a CDK4/6 inhibitor with IC50s of 3 and 1 nM, respectively. -
CDK12 inhibitor
CDK12-IN-3 is a potent and selective CDK12 inhibitor with an IC50 of 491 nM in enzymatic assay. -
CDK8/19 dual inhibitor
CDK8/19-IN-1 is a potent, selective and oral bioavailable CDK8/19 dual inhibitor, with IC50s of 0.46 nM, 0.99 nM and 270 nM for CDK8, CDK19 and CDK9, respectively.