Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Abstract

In addition to traditional drugs, such as enzyme inhibitors, receptor agonists/antagonists, and protein-protein interaction inhibitors as well as genetic technology, such as RNA interference and the CRISPR/Cas9 system, protein knockdown approaches using proteolysis-targeting chimeras (PROTACs) have attracted much attention. PROTACs, which induce selective degradation of their target protein via the ubiquitin-proteasome system, are useful for the down-regulation of various proteins, including disease-related proteins and epigenetic proteins. Recent reports have shown that chemical protein knockdown is possible not only in cells, but also in vivo and this approach is expected to be used as the therapeutic strategy for several diseases. Thus, this approach may be a significant technique to complement traditional drugs and genetic ablation and will be more widely used for drug discovery and chemical biology studies in the future. In this personal account, a history of chemical protein knockdown is introduced, and its features, recent progress in the epigenetics field, and future outlooks are discussed.

Keywords: Bromodomain; Drug design; Drug discovery; E3 ligase; Sirtuin.