Covalent inhibitors meet epigenetics: new opportunities

Epigenetic intervention has become an important therapeutic strategy for a variety of diseases, such as cancer. Although a small number of epigenetic drugs have been marketed, most of these inhibitors are limited by their poor efficacy, dose-dependent toxicity, poor selectivity, and drug resistance. The development of covalent inhibitors has progressed from questioning to resurgence. Its slow dissociation is expected to inject new vitality into epigenetic drugs. In this review, more than 40 covalent inhibitors of 29 epigenetic targets were collated, focusing on their design strategies, reaction mechanisms, covalent warheads and targeted amino acids, and covalent verification methods. Furthermore, this review presented new opportunities based on the current development of covalent inhibitors targeting epigenetic regulators. It is believed that epigenetic covalent inhibitors will lead to more breakthroughs.