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Publication Abstract from PubMed

Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from cofactor S-adenosylmethionine (SAM) to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a Ki value of 1.6+/-0.3 nM, which is the most potent inhibitor to date. The co-crystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.

Novel Propargyl-linked Bisubstrate Analogs as Tight-binding Inhibitors for Nicotinamide N-Methyltransferase.,Chen D, Li L, Diaz K, Iyamu ID, Yadav R, Noinaj N, Huang R J Med Chem. 2019 Nov 14. doi: 10.1021/acs.jmedchem.9b01255. PMID:31724854^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.