title: Chemical Inhibition of Protein Methyltransferases.
abstract: Protein methyltransferases (PMTs) participate in the epigenetic control of cell fate and other signaling pathways that are deregulated in disease, and the first PMT inhibitors have entered clinical trials in oncology. This review discusses structural studies that recently uncovered the mode of action of compounds in the clinic, as well as challenges and opportunities in the development of PMT inhibitors. It examines inhibitors that compete with the highly polar cofactor but preserve cell penetrance, and allosteric modes of inhibition. Vectors of optimization at the substrate-binding site and the potential of fragment screening approaches are discussed. Finally, the review presents strategies focused on targeting non-catalytic domains of PMTs or scaffolding subunits of chromatin complexes. Overall, although targeting PMTs remains a challenge, recent successes in the field are diverse and encouraging.
authors: Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: matthieu.schapira@utoronto.ca.
authors: Matthieu
authors: M
authors: Schapira
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011496:Protein Methyltransferases