Targeting Epigenetic Regulators with Covalent Small-Molecule Inhibitors

Abstract

Epigenetic regulation of gene expression plays a critical role in various physiological processes, and epigenetic dysregulation is implicated in a number of diseases, prominently including cancer. Epigenetic regulators have been validated as potential therapeutic targets, and significant progress has been made in the discovery and development of epigenetic-based inhibitors. However, successful epigenetic drug discovery is still facing challenges, including moderate selectivity, limited efficacy, and acquired drug resistance. Inspired by the advantages of covalent small-molecule inhibitors, targeted covalent inhibition has attracted increasing interest in epigenetic drug discovery. In this review, we comprehensively summarize the structure-based design and characterization of covalent inhibitors targeting epigenetic writers, readers, and erasers and highlight their potential benefits in enhancing selectivity across the enzyme family and improving in vivo efficacy. We also discuss the challenges and opportunities of covalent small-molecule inhibitors and hope to shed light on future epigenetic drug discovery.

Virtual Special Issue: Epigenetics 2022

“…What is notable about this collection of papers is the diversity of targets and approaches that are described. It is exciting to see a range of contemporary medicinal chemistry techniques applied to epigenetics targets, including covalent inhibitors, fragment-based approaches to ligand development, machine learning, and DNA-encoded libraries …”

Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer

“…Since covalent inhibitors can irreversibly bind to proteins and exert continuous inhibitory activity, they are expected to reduce the dosage and overcome drug resistance. 31,32 Inhibitors such as GNA002 and SKLB-0335 have been reported to covalently bind to EZH2 with moderate inhibitory activity. 33,34 However, the development of GNA002 (a gambogenic acid derivative) might be limited by its complex structure, large molecular weight, or low bioavailability.…”

Discovery of the First-in-Class G9a/GLP Covalent Inhibitors

“… , We hypothesized that this unexploited cysteine residue could be targeted to generate covalent inhibitors that may offer potential advantages over noncovalent inhibitors. While covalent inhibitors of G9a and/or GLP have not been reported, several epigenetic regulators have been successfully targeted by covalent inhibitors. − …”