Epigenetic polypharmacology: A new frontier for epi-drug discovery.

Recently, despite the great success achieved by the so-called "magic bullets" in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of "molecular network active compounds," embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi-epi-target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi-targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC-101 and CUDC-907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high-quality reviews on combination therapy and hybrid molecules. Hence, to update the state-of-the-art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi-epi-target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.