Chapter 4: Recent Developments in the Structural Mechanism of Protein Methyltransferase Inhibition

Protein methyltransferases are a therapeutic target class recently validated in the clinic. While medicinal chemistry strategies were originally focused on targeting the sites occupied by the methyl-accepting substrate or the methyl-donating cofactor, novel and equally promising modes of action and modalities have emerged in recent years. These include allosteric inhibitors exploiting the structural plasticity of the catalytic domain or targeting non-catalytic subunits of protein methyltransferase complexes. Methyl-lysine binding domains distal to the site of methyl transfer and involved in chromatin engagement or in the recruitment of activating peptides were also successfully exploited by PROTACs inducing the degradation of some of these enzymes. We focus here on inhibitors reported in the past four years to illustrate the latest developments in the structural chemistry of protein methyltransferase inhibition.