Molecular Pathways: Protein methyltransferases in cancer
Cet article passe en revue les travaux récents sur le développement d'inhibiteurs sélectifs de protéines méthyltransférases pour le traitement des cancers
The protein methyltransferases (PMTs) constitute a large and important class of enzymes that catalyze site-specific methylation of lysine or arginine residues on histones and other proteins. Site-specific histone methylation is a critical component of chromatin regulation of gene transcription - a pathway that is often genetically altered in human cancers. Oncogenic alterations (e.g., mutations, chromosomal translocations and others) of PMTs, or of associated proteins, have been found to confer unique dependencies of cancer cells on the activity of specific PMTs. Examples of potent, selective small molecule inhibitors of specific PMTs are reviewed that have been shown to kill cancers cells bearing such oncogenic alterations, while having minimal effect on proliferation of non-altered cells. Selective inhibitors of the PMTs DOT1L and EZH2 have entered phase 1 clinical studies and additional examples of selective PMT inhibitors are likely to enter the clinic soon. The current state of efforts towards clinical testing of selective PMT inhibitors as personalized cancer therapeutics is reviewed here.