Targeting epigenetic machinery: Emerging novel allosteric inhibitors

Abstract

Epigenetics has emerged as an extremely exciting fast-growing area of biomedical research in post genome era. Epigenetic dysfunction is tightly related with various diseases such as cancer and aging related degeneration, potentiating epigenetics modulators as important therapeutics targets. Indeed, inhibitors of histone deacetylase and DNA methyltransferase have been approved for treating blood tumor malignancies, whereas inhibitors of histone methyltransferase and histone acetyl-lysine recognizer bromodomain are in clinical stage. However, it remains a great challenge to discover potent and selective inhibitors by targeting catalytic site, as the same subfamily of epigenetic enzymes often share high sequence identity and very conserved catalytic core pocket. It is well known that epigenetic modifications are usually carried out by multi-protein complexes, and activation of catalytic subunit is often tightly regulated by other interactive protein component, especially in disease conditions. Therefore, it is not unusual that epigenetic complex machinery may exhibit allosteric regulation site induced by protein-protein interactions. Targeting allosteric site emerges as a compelling alternative strategy to develop epigenetic drugs with enhanced druggability and pharmacological profiles. In this review, we highlight recent progress in the development of allosteric inhibitors for epigenetic complexes through targeting protein-protein interactions. We also summarized the status of clinical applications of those inhibitors. Finally, we provide perspectives of future novel allosteric epigenetic machinery modulators emerging from otherwise undruggable single protein target.

Keywords: DNMT1; Epigenetics; MLL complex; PRC2; SWI/SNF; allosteric inhibitors.