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J Med Chem. 2018 Feb 22;61(4):1541-1551. doi: 10.1021/acs.jmedchem.7b01422. Epub 2018 Jan 31.

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).

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Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Accutar Biotechnology , Brooklyn, New York 11226, United States.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, People's Republic of China.
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.


Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-l-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays an important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6) and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.

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