An update on allosteric modulators as a promising strategy targeting histone methyltransferase

Histone methylation is a vital post-translational modification process in epigenetic regulation. The perturbation of histone methylation accounts for many diseases, including malignant cancers. Although achieving significant advances over past decades, orthosteric inhibitors targeting histone methyltransferases still suffer from challenges on subtype selectivity and acquired drug-resistant mutations. As an alternative, new compounds targeting the evolutionarily less conserved allosteric sites, exemplified by HKMTs and PRMTs inhibitors, offer a promising strategy to address this quandary. Herein, we highlight the allosteric sites and mechanisms in histone methyltransferases along with representative allosteric modulators, expecting to facilitate the discovery of allosteric modulators in favor of epigenetic therapy.