Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer.

08:00 EDT 12th April 2019 | BioPortfolio

Summary of "Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer."

The polypharmacology strategy of multi-targeting drugs acting on different biological pathways is capturing the researchers' attention, particularly in cancer. The simultaneous inhibition of two or more targets by drug combination or by a single 'hybrid molecule' can provide improved therapeutic efficacy when compared to the one-target inhibitors. In this regard, because of their multiple anticancer effects, histone deacetylase inhibitors have become a privileged tool for the development of hybrid drugs. The clinical trials of two multi-acting chimeras, HDAC/EGFR/HER2 and HDAC/PI3K inhibitors, encouraged the design of novel hybrids, such as compounds 22a (LSD1/HDAC) and 16a (CDK4/JAK1/HDAC), which showed superior anticancer effects than single-targeting agents or their combination both in cellular and mouse models.


Journal Details

This article was published in the following journal.

Name: Current opinion in chemical biology
ISSN: 1879-0402
Pages: 89-100


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Medical and Biotech [MESH] Definitions

Deacetylases that remove N-acetyl groups from amino side chains of the amino acids of HISTONES. The enzyme family can be divided into at least three structurally-defined subclasses. Class I and class II deacetylases utilize a zinc-dependent mechanism. The sirtuin histone deacetylases belong to class III and are NAD-dependent enzymes.

Compounds that inhibit HISTONE DEACETYLASES. This class of drugs may influence gene expression by increasing the level of acetylated HISTONES in specific CHROMATIN domains.

A subclass of histone deacetylases that are NAD-dependent. Several members of the SIRTUINS family are included in this subclass.

A class II histone deacetylase that removes acetyl groups from N-terminal LYSINES of HISTONE H2A; HISTONE H2B; HISTONE H3; and HISTONE H4. It plays a critical role in EPIGENETIC REPRESSION and regulation of GENETIC TRANSCRIPTION, as well as CELL MOTILITY through deacetylation of TUBULIN. It also targets misfolded proteins for clearance by AUTOPHAGY when MOLECULAR CHAPERONE-mediated folding is overwhelmed.

A multisubunit polycomb protein complex with affinity for CHROMATIN that contains methylated HISTONE H3. It contains an E3 ubiquitin ligase activity that is specific for HISTONE H2A and works in conjunction with POLYCOMB REPRESSIVE COMPLEX 2 to effect EPIGENETIC REPRESSION.

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