The Development of Epigenetics and Related Inhibitors for Targeted Drug Design in Cancer Therapy

Abstract

Epigenetics process is the heritable change in gene function that does not involve changes in the DNA sequence. Until now, several types of epigenetic mechanisms have been characterized, including DNA methylation, histone modification (acetylation, methylation, etc.), nucleosome remodeling, and noncoding RNAs. With the biological investigations of these modifiers, some of them are identified as promoters in the process of various diseases, such as cancer, cardiovascular disease and virus infection. Epigenetic changes may serve as potential “first hits” for tumorigenesis. Hence, targeting epigenetic modifiers is being considered as a promising way for disease treatment. To date, six agents in two epigenetic target classes (DNMT and HDAC) have been approved by the US Food and Drug Administration (FDA). Most of these drugs are applied in leukemia, lymphoma therapy, or are combined with other drugs for the treatment of solid tumor. Due to the rapid development of epigenetics and epigenetics targeted drugs, it is becoming an emerging area in targeted drug design.

Characterization of DNA hydroxymethylation profile in cervical cancer

“…As we know, DNA methyltransferases (DNMTs) contribute to the hypermethylation via the transfer of the methyl groups on the cytosines. Thus, DNMT inhibitors such as decitabine or azacytidine have been applied or combined with other drugs for the treatment of solid cancers [23]. Nevertheless, the persistently accumulated hypermethylation status of cancers also implies the other side that the process of DNA demethylation is blocking.…”

Nuclear Receptors Are Differentially Expressed and Activated in KAIMRC1 Compared to MCF7 and MDA-MB231 Breast Cancer Cells

“…Interestingly, the histone deacetylases (HDACs) are highly expressed in KAIRMC1 with HDAC6 and HDAC 7 expressed exclusively in KAIMRC1. Histone deacetylase inhibition constitutes an attractive therapeutic strategy for breast cancer [58]. Similarly to coactivators, some co-repressors of nuclear receptors have been shown to have altered expression in breast cancer.…”

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

“…1) and a wide range of epigenetic-based drugs are undergoing clinical trials. These include 5-azacytidine (1, DNMT inhibitor approved for the treatment of MDS) [66], 5-Aza-2-deoxycytidine (2, DNMT inhibitor approved for the treatment of MDS) [66], FK-228 (3, HDAC inhibitor approved for the treatment of refractory CTCL) [67], SAHA (4, HDAC inhibitor approved for the treatment of refractory CTCL) [68], PXD101 (5, HDAC inhibitor approved for the treatment of refractory PTCL) [69], LBH589 (6, HDAC inhibitor for the treatment of multiple myeloma) [70] and tazemetostat (7, EZH2 inhibitor approved for the treatment of metastatic or locally advanced epithelioid sarcoma) [71]. Other than the aforementioned FDA approved agents, an anilide type HDAC inhibitor, chidamide (8), has also been approved by CFDA to treat patients with R/R PTCL [72].…”

“…DNMT blockade is considered to be a successful strategy for the prevention of aberrant DNA hypermethylation. DNMT inhibitors reactivate the aberrantly methylated TSG, thereby causing cancer cells reprogramming that ultimately lead to proliferation arrest and cell death [73,74]. Literature precedents indicate that various compounds have been identified both at the preclinical as well as clinical level that can erase abnormal methylation patterns via irreversible inhibition of DNMTs, causing proteosomal degradation [75,76].…”