Protein Methyltransferase Inhibitors as Personalized Cancer Therapeutics

The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example: gene amplification, chromosomal translocations, point mutations, and synthetic lethal relationships [Copeland et al. (2013) Oncogene 32: 939-946]. The enzymes DOT1L and EZH2 provide two representative examples of altered PMTs that act as genetic drivers of specific human cancers. The enzymatic activity of DOT1L is associated with a chromosomal translocation that is universally found in patients with MLL-rearranged leukemia [Daigle et al. (2011) Cancer Cell 20: 53-65; Daigle et al. Blood, prepublished June 25, 2013; doi:10.1182/blood-2013-04-497644]. Point mutations at Y641 of EZH2 are found in a subset of non-Hodgkin lymphoma patients; the enzymatic activity of both wild-type and mutant EZH2 are required for pathogenesis in these patients [Sneeringer et al. (2010) Proc. Natl. Acad. Sci. USA 107: 20980-20985; Knutson et al. (2012) Nature Chem. Biol. 8: 890-896]. Also, deletion of the SMARCB1 subunit of the SWI/SNF chromatin-remodeling complex occurs in nearly all malignant rhabdoid tumors (MRTs), a childhood cancer with a particularly poor prognosis. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the SMARCB1 deletion. MRTs therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation and we have shown that MRT cells deficient in SMARCB1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models [Knutson et al. (2013) Proc. Natl. Acad. Sci. USA 110: 7922-7927]. Drug discovery efforts have yielded potent, selective inhibitors of each of these targets that have now transitioned into phase I clinical trials. These inhibitors affect the appropriate histone methyl marks in cells, lead to selective cell killing that is dependent on genetic alteration of the target enzyme, and effect tumor growth inhibition in xenograft models. These data portend the effective use of selective PMT inhibitors as a novel modality for future personalized cancer therapeutics.