Molecular Design of Compounds Targeting Histone Methyltransferases

Research on cancer epigenetics has flourished in the last decade as growing evidence points to the importance of understanding the mechanisms by which epigenetic changes regulate the genesis and progression of several pathologies, especially cancer. Several epigenetic targets have been discovered and are currently under validation for different therapies. In this context, drug discovery approaches aiming at developing new small-molecule modulators have produced the first preclinical and clinical outcomes and many other compounds are now entering the pipeline as new epi-drugs. While most of the efforts have been dedicated in the past to histone deacetylases and DNA methyltransferases, other classes of enzymes are also likely to represent new frontiers for therapeutic interventions. In this chapter we describe the increasing importance of histone methyltransferases in the drug discovery arena and discuss the drug design perspectives enabled by computational techniques to develop new small-molecule inhibitors for these classes of enzymes.