title: Inhibitors of protein methyltransferases as chemical tools.
abstract: Protein methyltransferases (PMT)s play essential roles in many biological processes through methylation of histones and diverse nonhistone substrates. Dysregulation of these enzymes has been implicated in many diseases including cancers. While PMT-associated biology can be probed via genetic perturbation, this approach targets full-length PMTs rather than their methyltransferase activities and often lacks temporal, spatial and dose controls (timing, location and amount of dosed compounds). By contrast, small-molecule inhibitors of PMTs can be designed to specifically target the methyltransferase domains in a temporal, spatial and dose-dependent manner. This utility has motivated the development of hundreds of PMT inhibitors, but meanwhile can make it challenging to select the most suitable PMT inhibitors to interrogate PMT-associated biology. This perspective aims to provide timely guidance to evaluate these PMT inhibitors in their relevant biological contexts.
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation / Q000187:drug effects; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D011496:Protein Methyltransferases
keywords: MOA; PKMT; PRMT; chemical probe; off-target effects; target engagement