Targeting cancer metastasis through isoform selective HDAC inhibitors

Abstract

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible.This implies that they are amenable to pharmacological interventions. Recently, epigenetic regulation has been shown to play a role in cancer cell migration and invasion through the action of histone deacetylase (HDAC) enzymes, particularly some isoforms. Our objective is to design potent and selective inhibitors of these isoforms, and explore their ability to inhibit cell migration. These compounds will be novel leads that selectively target the cell migration process while avoiding the side effect profile observed with non-selective clinically approved HDAC inhibitors. (AU)