Design of histone methyltransferase and deacetylase modulators: applications in cancer and non-cancer diseases

In our two previous studies, we reported the discovery and the optimization of novel 1,4-dihydropyridine-based sirtuin ligands. Starting from SIRT1-activating 1,4-DHPs, bearing benzyl group at N1, we identified carbonyl group at N1 to be responsible for an increased SIRT3 activation (MC2791 (1a) and MC2789 (1u)). However, the moderate potencies of 1a and 1u prompted us to screen for more potent derivatives. We generated new series of compounds by varying their “top” or “bottom” with other substituents at C1 or C4 position of the DHP scaffold, respectively. Hence, we reported the discovery and characterization of potent and specific activators for Sirt3 and/or Sirt5. The 1,4-DHP-based activators bind to the sirtuin catalytic core independent of bound substrates and increase the enzyme’s turnover. The compounds are selective for Sirt3 or Sirt5 and show cellular activity. Overall, our results provided a scaffold for potent and specific sirtuins activation and an activation model for Sirt3 and Sirt5 as a basis for functional studies and further drug development. Additionally, HBV-infected cells treated with our potent and selective Sirt3 activator 1a, demonstrated that 1a regulates the antiviral activity of cccDNA in HepAD38 cells. The treatment of HBV-infected cells with 1a through SIRT3 stimulation led to histone H3 and/or H4 hypoacetylation and reduction in the transcription from a viral cccDNA template, accompanied by a reduction in HBV replication. Together these results indicate that the Sirt3 activator 1a can modulate the acetylation status of cccDNA-bound H3/H4 histones, thus providing a novel therapeutic approach for the treatment of chronic HBV infection.