Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives

Abstract

Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.

Fig. (1)

Connections between classes of epigenetic targets with cancer diseases and drug discovery information. Known ligands, clinical trials and approved drugs refer to cancer therapies with mechanisms of action directly related to epigenetic targets. Clinical trials and approved drugs have been recently reviewed in [46].

Fig. (2)

Depiction of SAM and histone binding sites of SETD8 methyltranferase. Assessing the mode of action implies a full understanding of the more appropriate mechanism of inhibition operated by small-molecules.