Recent Advances in enhancer of zeste homolog 2 Inhibitors: Structural insights and therapeutic applications

Abstract

Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in many malignancies and plays a critical role in cancer progression. Therefore, it is considered a promising target for therapeutic intervention. Although several EZH2 inhibitors have entered clinical trials, only one has received FDA approval. In this review, we focus on the latest advancements in highly selective and potent dual-targeting EZH2 inhibitors, as well as proteolysis-targeted chimeras (PROTACs) and hydrophobic tagging (HYT) degraders. These novel compounds have been developed to address the existing gaps in the management of abnormal EZH2 expression. Notably, EZH2 inhibitors have shown great efficacy in antitumor therapy and have also demonstrated promising results in antiviral, anti-inflammatory, antisclerotic, bone protection, and nerve injury pain applications. The insights gained from this analysis could provide valuable guidance for future drug design and optimization of EZH2 inhibitors, potentially expediting the discovery of new inhibitors or degraders targeting EZH2.

Keywords: Dual-targeting EZH2 Inhibitors; EZH2 Inhibitors; Hydrophobic Tagging; Nonantitumor Activity; Proteolysis-Targeted Chimera.