CHAPTER 8: Progress in Targeting Epigenetic Readers

Histone modifications are ‘read’ by protein modules which recognise defined modification states and act as scaffolds to attract protein complexes that further alter the epigenetic architecture at a specific location. This leads to enhanced or repressed gene expression. The dogma that it would be impossible to target these protein–protein interactions has recently been overturned, first by the discovery of potent small molecule inhibitors of bromodomains, the readers of acetylated histones, and more recently by inhibitors of methyl-lysine reader proteins of the ‘Royal’ and WD40r families. This chapter will present case studies of how these inhibitors have emerged from, and the merits of, a variety of hit discovery approaches including phenotypic screening, structure and fragment-based drug design and peptide mimicry. A view of the therapeutic value and biological challenges of targeting reader domains, as well as the utility of emerging biological and chemical tools will also be given.