Discovery of protein degraders targeting lysine modification enzymes

Abstract

Lysine-modifying enzymes―such as histone acetyltransferases (HATs), histone deacetylases (HDACs), lysine methyltransferases (KMTs), and lysine demethylases (KDMs)―regulate a wide range of cellular processes and are implicated in various diseases. As such, they have long been considered attractive therapeutic targets. Traditionally, drug discovery efforts have focused on developing inhibitors that block the enzymatic activity of these proteins. However, growing evidence suggests that inhibiting catalytic activity alone is often insufficient to achieve meaningful or lasting biological outcomes in cellular or disease models. Recent studies have shown that many lysine-modifying enzymes also act as scaffolding proteins, forming multiprotein complexes with transcription factors and chromatin-associated proteins. Through these non-catalytic interactions, they influence gene expression, chromatin organization, and cellular phenotypes. These findings underscore the limitations of conventional enzyme inhibition strategies and highlight the need for new therapeutic approaches that can suppress both the catalytic and non-catalytic functions of these proteins. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising solution to this challenge. PROTACs are bifunctional molecules that promote the selective degradation of target proteins via the ubiquitin–proteasome system. Unlike traditional inhibitors, PROTACs eliminate the entire target protein, thereby disrupting all associated functions, both enzymatic and scaffolding. This mode of action can produce distinct biological effects and may offer therapeutic benefits that cannot be achieved through inhibition alone. In this article, we highlight PROTAC-based strategies targeting key lysine-modifying enzymes, including HDAC8, G9a/GLP, and KDM5C. By summarizing our recent work on the design and biological evaluation of these degraders, we demonstrate how targeted protein degradation can deepen our understanding of protein function and open new avenues for therapeutic development beyond conventional inhibition.