Epigenetic writers are enzymes that catalyze the addition of chemical groups, such as methyl or acetyl groups, to DNA or histone proteins. These modifications, including methylation and acetylation, regulate gene expression by altering chromatin structure. Epigenetic writer inhibitors have gained significant attention for their therapeutic capability, particularly in cancer treatment. These inhibitors also show potential beyond oncology, including their application in treatment of inflammatory diseases, neurological disorders, and regenerative medicine, as they help modulate key pathways involved in cellular differentiation and immune responses.
Our cheminformatics team developed a specialized selection of over 30,500 small-molecule screening compounds tailored to target key epigenetic writers (Fig. 1). Those predicted target-specific inhibitors of DNA and histone-modifying enzymes do not contain PAINS, toxic and reactive groups.
Using internal similarity metrics and the Tanimoto matrix, we also offer a Diversity Screening Subset of approximately 3,200 potential epigenetic writer inhibitors. This subset provides efficient access to a pool of structurally diverse small molecules, carefully selected based on their similarity to the most potent reference compounds.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure 1. Compound distribution protein targets within the Epigenetic Writer Screening Library.
Representative screening compounds from the Screening Library
Background information
There are several groups of proteins that are linked to the epigenetic writing process playing their key role in gene activation and repression. These enzymes have important implications in cellular processes, such as differentiation, development, and the pathology of diseases.
- DNA Methyltransferases (DNMTs) transfer methyl groups to cytosines in CpG islands of DNA, typically leading to transcriptional repression. Main enzymes include DNMT1, DNMT3A [4].
- Histone Methyltransferases (HMTs) catalyze the methylation of lysine or arginine residues on histones. Important HMTs include MLL family [5], and EZH2 [6], which methylate histone H3 at lysine 9, and lysine 27, respectively.
- Histone Acetyltransferases (HATs) add acetyl groups to lysines on histone tails, neutralizing their positive charge and relaxing chromatin structure, facilitating gene expression. Notable HATs include GCN5 and PCAF [7].
DNA methyltransferases (DNMTs), histone methyltransferases (HMTs) and other epigenetic enzymes are often dysregulated in cancers, leading to abnormal gene silencing or activation. For instance, DNMT inhibitors, such as 5-azacytidine and decitabine, are FDA-approved treatments for myelodysplastic syndrome and certain leukemias, where they reverse abnormal DNA hypermethylation that silences tumor suppressor genes [1]. Similarly, histone methyltransferase inhibitors, such as those targeting EZH2, have shown promise in combating chemoresistance and halting tumor growth in various malignancies. EZH2 inhibitors restore normal gene regulation by reversing excessive methylation marks associated with cancer progression. Moreover, inhibitors of protein arginine methyltransferases (PRMTs), like PRMT5, are under investigation for their role in limiting cancer cell proliferation and survival, especially in hematologic malignancies [2]. Their continued development highlights the importance of targeting epigenetic writers to address a wide range of pathologies [3].
Compound selection
First, a reference compound set focused on methyltransferases, acetyltransferases, and PARPs derived from the ChEMBL database was prepared. It was followed by a similarity search against the Life Chemicals HTS Compound Collection with the Tanimoto index ≥ 0.80 using ECFP fingerprints. The final screening set features 30,500 drug-like screening compounds designed to cover the most relevant enzymatic drivers of chromatin modification and RNA methylation.
Epigenetic writer targets covered
DNA Methyltransferases (DNMTs)
- DNMT1
- DNMT3A
Histone Acetyltransferases (HATs)
- CREB-binding protein (CBP)
- p300
- GCN5
- PCAF
- Nuclear receptor coactivator 3
Histone Lysine Methyltransferases (KMTs)
- ASH1L
- EZH2
- MLL (including Menin–MLL complex)
- NSD2
- SETD7
- SETD8
- SMYD2
- SMYD3
- SUV39H1
- SUV39H2
- SUV420H2
- DOT1L (H3K79-specific)
- H3K9-specific methyltransferases (e.g., SUV39 family members)
Protein Arginine Methyltransferases (PRMTs)
- PRMT1
- PRMT5 (including PRMT5/MEP50 complex)
- PRMT6
- CARM1 (PRMT4)
RNA Methyltransferases
- N6-adenosine methyltransferase catalytic subunit (METTL3-related activity)
- rRNA adenine N6-methyltransferase
Small-Molecule & Metabolic Methyltransferases
- Catechol O-methyltransferase (COMT)
- Histamine N-methyltransferase
- Nicotinamide N-methyltransferase (NNMT)
- Phenylethanolamine N-methyltransferase (PNMT)
- Isoprenylcysteine carboxyl methyltransferase
- N-terminal Xaa-Pro-Lys N-methyltransferase 1
Figure 2. Epigenetic regulation through writers, readers and erasers.
Reference:
- Ocaña-Paredes B, Rivera-Orellana S, Ramírez-Sánchez D, Montalvo-Guerrero J, Freire MP, Espinoza-Ferrao S, Altamirano-Colina A, Echeverría-Espinoza P, Ramos-Medina MJ, Echeverría-Garcés G, Granda-Moncayo D, Jácome-Alvarado A, Andrade MG, López-Cortés A. The pharmacoepigenetic paradigm in cancer treatment. Front Pharmacol. 2024 Apr 24;15:1381168. doi: 10.3389/fphar.2024.1381168.
- Gan, L., Yang, Y., Li, Q. et al. Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark Res 6, 10 (2018). https://doi.org/10.1186/s40364-018-0122-2.
- Feehley, T., O’Donnell, C.W., Mendlein, J. et al. Drugging the epigenome in the age of precision medicine. Clin Epigenet 15, 6 (2023). https://doi.org/10.1186/s13148-022-01419-z.
- Robertson, K D et al. “The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors.” Nucleic acids research vol. 27,11 (1999): 2291-8. doi:10.1093/nar/27.11.2291
- Ballabio, Erica, and Thomas A Milne. “Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis.” Cancers vol. 4,3 904-44. 10 Sep. 2012, doi:10.3390/cancers4030904.
- Cao, Ru et al. “Role of histone H3 lysine 27 methylation in Polycomb-group silencing.” Science (New York, N.Y.) vol. 298,5595 (2002): 1039-43. doi:10.1126/science.1076997.
- de Jong, Rob C M, et al. “The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development.” PloS one vol. 12,10 e0185820. 10 Oct. 2017, doi:10.1371/journal.pone.0185820.