Drug Development in Cancer Epigenetics

Classic Anti-cancer Epigenetic Drugs
The two most classic anti-cancer epigenetic drugs are DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi).
• DNA methyltransferase inhibitor (DNMTi)
DNA methylation is catalyzed by DNA methyltransferases (DNMTs), using S-adenosylmethionine (SAM) as the methyl donor, and adding a methyl group to the fifth carbon of the cytosine residue in CpG dinucleotides. And DNA methylation is an epigenetic modification that silences genes. However, abnormal methylation occurs in tumor cells, where will present genome-wide hypomethylation and hypermethylation of specific gene to a certain extent. Based on the importance of DNMT, various drugs targeting DNMT have been developed and successively entered clinical trials.
These drugs prevent the addition of methyl groups to genes of tumor cells and reactivate hypermethylated tumor suppressor genes. There are two types of DNMTi, one of which is the nucleotide analog that binds to DNA to form a covalent complex. The complex will promote the degradation of DNMT. Both Azacitidine and Decitabine belong to this type of DNMT and have undergone more than 200 clinical trials related to leukemia and solid tumors. They have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CML), and myelodysplastic syndrome (MDS). DNMTis are of great significance in treating cancers with hypermethylation in the promoter region of genes (Table 1).

Table 1 FDA-approved epigenetic drugs inhibiting DNMT for cancer therapy

Drug Name Approved Year Company Indicated Disease Signaling Pathways Affected
Azacitidine (Vidaza) 2004 Celgene AML, CML and MDS Wnt, MDA5/MAVS/IRF7 signaling pathway
Decitabine (Dacogen) 2006 Astex Pharmaceuticals AML, CML and MDS MAPK, PI3K-Akt, TGF-β, ERK, NGFR signaling pathway

• Histone deacetylase inhibitor (HDACi)
Acetylation is one of the most common post-translational modifications of histones. Histone acetylation is regulated by two families of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC stabilizes the dense structure of chromatin by the deacetylation (removal of acetyl groups) of histones, making these DNA regions less accessible to gene transcription factors. As a result, the expression of proteins involved in cell differentiation, cell cycle arrest, tumor immunity, and apoptosis of damaged cells is inhibited, all of which will promote the development of cancer. HDACi works by controlling how tightly the DNA binds to the histones. Drug development examples of HDACi include Vorinostat for the treatment of refractory or relapsed cutaneous T cell lymphoma (CTCL), Belinostat for the treatment of peripheral T-cell lymphoma (PTCL), and Romidepsin for both CTCL and PLCL, which have been approved by the FDA for clinical use (Table 2).

Table 2 FDA-approved epigenetic drugs inhibiting HDAC for cancer therapy

Drug Name Approved Year Company Indicated Disease Signaling Pathways Affected
Vorinostat (Zolinza) 2006 Merck CTCL ROS-dependent apoptosis, p21 signaling pathway
Romidepsin (Istodax) 2009 Celgene CTCL AKT signaling pathway
Belinostat (Beleodaq) 2015 Acrotech PTCL MAPK, TGF-β signaling pathway
Panobinostat (Farydak) 2015 Secura Multiple Myeloma (MM) EGFR/HER2, MAPK, PI3K-Akt, NFκB signaling pathway

Novel Drug Targets for Cancer Epigenetics
In terms of drug target selection, many examples of drug discovery targeting new cancer epigenetic mechanisms have emerged in recent years. Potential drugs developed based on these new mechanisms include enhancer of zeste homolog 2 (EZH2) inhibitors, disruptor of telomeric silencing 1-like (DOT1L) inhibitors, bromodomain and extra-terminal protein (BET) inhibitors, nuclear receptor binding SET domain protein 2 (NSD2) inhibitors, lysine-specific histone demethylase 1A (LSD1/KDM1A) inhibitors, protein arginine methyltransferase (PRMT) inhibitors and inhibitors of the mutant isocitrate dehydrogenase (IDH), etc.
Drug Development Challenges
First, epigenetic mechanisms are sophisticated, for instance, mutated epigenetic factors do not only modify a certain gene, histone, and chromatin. Therefore, it’s necessary to illuminate a comprehensive understanding of epigenomic dysregulation in specific cancer types. Second, specificity is one of the challenges in the development of cancer epigenetic drugs. For example, when DMNTi is used to reactivate suppressed tumor suppressor genes, there is also a risk of overexpression of oncogenes. In addition, the effect of individual factors on epigenetic drug efficacy needs further study.
Future Outlook
Although there are still many problems to be solved urgently, compared with traditional anti-cancer drug treatment, epigenetic therapy shows certain advantages. In response to tumor immune escape, it was found in early clinical trials that some epigenetic drugs can effectively stimulate the expression of major histocompatibility complex (MHC) and enhance the killing effect of effector T cells on tumors. Therefore, in the immunotherapy, the combination of epigenetic drugs can achieve the purpose of improving efficacy. On the other hand, the resistance of traditional anticancer drugs has always been a difficult problem to solve, while epigenetic drugs can inhibit the development of drug resistance, and at the same time, epigenetic drugs can directly suppress or kill the cancer cells that have developed resistance. At present, hundreds of epigenetic drugs for cancer therapy have entered various stages of clinical trials, and among them, most of the drugs are in early clinical trials. It is believed that more and more epigenetic drugs will be approved for marketing in the next few years, and such emerging drugs are bound to inject new vitality into the field of cancer therapy.
To promote your cancer epigenetics drug development programs, Creative BioMart provides a full range of biological tools (including but not limited to high-quality recombinant proteins, synthetic peptides, nucleosomes, antibodies related to histones or epigenetic modification enzymes) and chemical tools (such as selective inhibitors/activators and compound libraries for screening small molecule modulators of epigenetic enzymes). We have rich experience for over 10 years and currently are capable of providing biochemical and cell-based assays of epigenetic lead compounds, as well as contract research services for cancer epigenetics drug discovery projects.

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2. Campbell R M, Tummino P J. Cancer epigenetics drug discovery and development: the challenge of hitting the mark. The Journal of Clinical Investigation. 2014, 124(1): 64-69.
3. Pechalrieu D.; et al. DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies. Biochemical Pharmacology. 2017, 129: 1-13.
4. Garmpis N.; et al. Targeting histone deacetylases in malignant melanoma: a future therapeutic agent or just great expectations? Anticancer Research. 2017, 37(10): 5355-5362.
5. Srinivas Patnaik A. Drugs targeting epigenetic modifications and plausible therapeutic strategies against Colorectal Cancer. Frontiers in Pharmacology. 2019, 10.

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