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

Giulia Stazi; Rossella Fioravanti; Antonello Mai; Andrea Mattevi; Sergio Valente

doi:10.1016/j.cbpa.2019.03.002

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

Curr Opin Chem Biol. 2019 Jun:50:89-100. doi: 10.1016/j.cbpa.2019.03.002. Epub 2019 Apr 12.

Authors

Giulia Stazi¹, Rossella Fioravanti¹, Antonello Mai², Andrea Mattevi³, Sergio Valente⁴

Affiliations

¹ Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
² Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy; Pasteur Institute - Cenci Bolognetti Foundation, Sapienza Università di Roma, Viale Regina Elena 324, 00161 Rome, Italy. Electronic address: antonello.mai@uniroma1.it.
³ Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy. Electronic address: andrea.mattevi@unipv.it.
⁴ Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy. Electronic address: sergio.valente@uniroma1.it.

PMID: 30986654
DOI: 10.1016/j.cbpa.2019.03.002

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antineoplastic Agents / therapeutic use*
Epigenesis, Genetic*
Histone Deacetylase Inhibitors / therapeutic use*
Histone Deacetylases / metabolism*
Humans
Neoplasms / drug therapy*

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Histone Deacetylases