The epigenetic 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 single-target inhibitors. In this regard, because of their multiple anticancer effects, histone deacetylase (HDAC) inhibitors have become a privileged tool for the development of hybrid drugs. Hence, the clinical trials of two multi-acting chimeras, HDAC/EGFR/HER2 and HDAC/PI3K inhibitors, encouraged us to design novel hybrids, such as compound corin, the first-in-class dual LSD1/HDAC inhibitor, which showed superior anticancer effects than single-targeting agents or their combination both in cellular and mouse models. Furthermore, recently the synergistic antiproliferative effects observed by simultaneous HDAC and EZH2 inhibition prompted our group to discover the first-in-class HDAC/EZH2 hybrid inhibitor MC4128, able to display a promising anticancer profile. Moreover, a new strong synergism was highlighted by the co-treatment with LSD1 and PRMT5 inhibitors. Based on these findings, the aim of the present project is to develop new dual HDAC/LSD1, HDAC/EZH2 and LSD1/PRMT5 hybrid inhibitors to fight cancer diseases. The new chemical entities will be tested in biochemical, cellular and mouse settings.