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.
Although HDACi reached the FDA approval for cancer treatment, these drugs are not endowed with good efficacy in solid cancers. However, recent studies proved synergistic effects when administered in combination with other classical chemotherapeutics or epigenetic drugs, leading to highly improved anticancer efficacy both in preclinical and clinical settings.1, 5 These findings prompted the researchers to design dual targeting hybrid molecules, which simultaneously inhibits two different targets involved in convergent cancer pathogenesis pathways, mainly epigenetic, as the last studies highlight.1, 5 Some of these approaches achieved solid results in cancer treatment,1 arousing our interest, even considering that our research group has 20 years experienced research in epigenetic targets, 23 to design new hybrid prototypes, targeting HDAC and LSD1, which biophysically interact in corepressor complex and whose first-in-class dual inhibitor has already shown promising improved potential with respect to both single agents and the single agent combinations. Moreover, other than HDAC and LSD1, EZH2 is another epigenetic target under very strong biological/pharmacological investigation, whose inhibitor tazemetostat has just got FDA-approval. In this issue, our group very recently discovered the first-in-class EZH2/HDAC dual inhibitor,13 displaying interesting results and hence deserving a following optimization study. Together with the dual HDAC/LSD1, the dual EZH2/HDAC inhibition could be useful for not only to achieve a significant improvement in the cancer treatment efficacy or to overcome drug resistance, but also to better understand the new possible convergent biological molecular mechanism in cancer pathogenesis to be targeted in the future investigations. Another critical target in epigenetic-based cancer treatment is represented by PRMT5, since some of its inhibitors already entered the clinical arena. Moreover, recently it has been proven that the combination of LSD1 and PRMT5 inhibition can provide synergism of action in leukemia cells, thus justifying our plan to synthesize the first-in-class LSD1/PRMT5 hybrid inhibitors, as useful tool to reveal the real biological potential of the two targets.
Taken together, the dual-targeting hybrid molecules developed by us in this project will allow the improvement of the knowledge of epigenetic mechanisms that lie under cancer pathogenesis, but also could offer new therapeutic strategies with improved efficacy in preclinical studies.
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