Synthesis and bioactivity of novel histone acetylation inhibitors. Potential new drugs for treatment of cancer and inflammation

PhD ceremony: Mr. M. Ghizzoni, 16.15 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Synthesis and bioactivity of novel histone acetylation inhibitors. Potential new drugs for treatment of cancer and inflammation

Promotor(s): prof. H.J. Haisma

Faculty: Mathematics and Natural Sciences

There is an increasing interest in histone acetyltransferases (HATs) as new therapeutic targets for treatment of diseases like, for example, inflammation and cancer. However, only few small and cell-permeable molecule inhibitors of HATs are currently available. The work described in the thesis of Massimo Ghizzoni focuses on the synthesis and biological evaluation of novel HAT inhibitors. The major challenge is to find potent and selective HAT inhibitors that show biological activity in cells.

In the first part of his thesis he reports the design and synthesis of potent isothiazolone-based inhibitors of the recombinant HAT PCAF, which are also cytotoxic for different cancer cell lines. Moreover, he elucidates the chemical reactivity of isothiazolones derivatives showing that isothiazolones might find applications in activity-based protein profiling studies.

The second part of Ghizzonis thesis describes the development of novel HAT inhibitors using the natural product anacardic acid (AA) as starting point. Using a combination of molecular design, organic synthesis and enzyme inhibition studies, he has developed several novel compounds that are selective inhibitors of the recombinant HAT Tip60 in comparison with the HATs PCAF and p300. Furthermore, he has identified a new AA derivative that shows a two-fold improved potency for inhibition of histone H4 acetylation in cell-based studies.

In conclusion, the work described in the thesis of Ghizzoni provides new chemical tools for pharmacological studies to validate HATs inhibitors as potential new drugs for treatment of cancer and inflammation.