Synthesis And Assays of SAM-Based Inhibitors of Methyltransferases

Gene expression and transcription are critical for a variety of cellular processes and are controlled not only by DNA sequence and transcription factors but also by epigenetic regulation¹. Epigenetic regulation requires site-specific modification of the genome and is involved in multiple physiological processes and disease etiology¹. Methyltransferases, which catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to various substrates (figure 1), are critical components of the epigenetic regulation². This group of enzymes can methylate diverse substrates including DNA, RNA, proteins, and small-molecule metabolites³. This presentation will focus on protein methyltransferases (PMTs). The PMTs’ dysregulation has also been implicated in multiple disease states such as cancer, neurological, and cardiovascular disorders. Developing potent and selective small-molecule inhibitors of PMTs are valuable not only for therapeutic intervention but also for investigating the roles of these enzymes in disease progression¹.  In this presentation, the strategies of designing and synthesizing PMTs’ inhibitors based on the SAM scaffold will be discussed. Based on the basis of characteristic substitutions at the 5’-position of SAM, current SAM-based analogs can be classified into five categories: 5’-alkylthio, 5’-alkoxy, 5’-alkyl/alkenyl, 5’-aminoalkyl, and 5’-amino analogs². In general, the types of 5’-substitutions are crucial for the potency and selectivity for inhibiting PMTs as demonstrated by the EZH2 inhibitor, and DOT1L inhibitor EPZ004777. Here, the synthetic strategies to construct the diverse 5’-substitutions as well as nucleosides, amino acids, and 6’-amino group (for 5’-aminoalkyl analogs) of SAM mimics in the context of optimizing potency and selectivity against specific PMT targets will be discussed. Their structure–activity relationships (SARs) and underline key modifications on these SAM scaffolds will be presented as well.

References:

1. Luo. ACS Chem. Biol. 2012, 7 ,443-463.
2. Luo et al. Methods in Enzymology. 2016, 574, 245-308.
3. Kaniskan et al. Chem. Rev. 2018, 118, 989−1068