title: Synthesis and Assays of Inhibitors of Methyltransferases.
abstract: Epigenetic regulation requires site-specific modification of the genome and is involved in multiple physiological processes and disease etiology. Methyltransferases, which catalyze the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to various substrates, are critical components of the epigenetic machinery. This group of enzymes can methylate diverse substrates including DNA, RNA, proteins, and small-molecule metabolites. Their dysregulation has also been implicated in multiple disease states such as cancer, neurological, and cardiovascular disorders. Developing potent and selective small-molecule inhibitors of methyltransferases is valuable not only for therapeutic intervention but also for investigating the roles of these enzymes in disease progression. In this chapter, we will discuss the strategies of designing and synthesizing methyltransferases inhibitors based on the SAM scaffold. Following the section of inhibitor design, we will briefly review representative assays that are available to evaluate the potency of these inhibitors along with a detailed description of the most commonly used radiometric assay.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: X-C
authors.initials: XC
authors.lastname: Cai
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: K
authors.initials: K
authors.lastname: Kapilashrami
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: luom@mskcc.org.
authors.forename: M
authors.initials: M
authors.lastname: Luo
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057075:Enzyme Assays / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008780:Methyltransferases
keywords: Epigenetics; Inhibition; Methylation; S-Adenosyl-l-homocysteine; S-Adenosyl-l-methionine; Sinefungin; Structure-based inhibitor design