Exploring Methods of Targeting Histone Methyltransferases andTheir Applications in Cancer Therapeutics br

Histone methyltransferases (HMTs) are enzymes that catalyze the methylation of lysine or arginine residues ofhistone proteins, a key post-translational modification (PTM). Aberrant expression or activity of these enzymes can lead to abnormalhistone methylation of cancer-related genes and thus promote tumorigenesis. Histone methyltransferases have been implicated inchemotherapeutic resistance and immune stimulation, making these enzymes potential therapeutic targets of interest, and chemicallytargeting these proteins provides an avenue for novel drug development in cancer therapy. This Review aims to discuss the evolutionof chemical approaches that have emerged in the pastfive years to design probes targeting these enzymes, including inhibitionthrough noncovalent inhibitors, covalent inhibitors, and targeted protein degradation through proteolysis targeting chimeras(PROTACs). This Review also highlights how these compounds have been used to study the myriad of HMT functions in cancerprogression and treatment response. The recent advancement of some of these drugs into human clinical investigation and even toregulatory approval highlights HMTs as a promising class of targets for chemical intervention and novel therapy development.