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Together is Better: Epigenetic Polypharmacology

Abstract: Recently, despite the great success achieved by the “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 compounds able to simultaneously hit multiple targets related and/or involved in the same disease (polypharmacology).1 The multi-targeting approach can overcome some 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. 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. Multitargeting single drugs are the result of the conjugation of two or more active molecules that individually show a known activity against specific targets. This can be achieved either by connecting molecules with a linker cleaved in physiological conditions (mutual prodrugs), or connecting molecules with a stable linker, allowing each molecular moiety to interact with its specific target without interfering with the interactions established by the other portion, or merging molecules together, preserving and connecting in the final multitarget ligand only functional and reactive groups (warheads). 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, or one epi-target and another target not related to epigenetics. To date, two dual histone deacetylase/kinase inhibitors (CUDC-101 and CUDC-907) are in clinical trials for treatment of cancer. In the lecture, we will discuss our experience in epi-polypharmacology, from the first hybrids ATRA/HDAC inhibitors to pan-KDM inhibitors, dual HAT/EZH2 and HDAC/EZH2 inhibitors, dual HDAC/LSD1 and G9a/LSD1 inhibitors, all useful to fight cancer diseases.

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