2. Academic Validation
  3. Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

  • J Med Chem. 2019 Jul 25;62(14):6597-6614. doi: 10.1021/acs.jmedchem.9b00413.
Yongzhi Gao 1,  Matthijs J van Haren 1,  Ed E Moret,  Johannes J M Rood,  Davide Sartini 2,  Alessia Salvucci 2,  Monica Emanuelli 2,  Pierrick Craveur 3,  Nicolas Babault 3 4,  Jian Jin 4,  Nathaniel I Martin 1
Affiliations

Affiliations

  • 1 Biological Chemistry Group, Institute of Biology Leiden , Leiden University , Sylviusweg 72 , 2333 BE Leiden , The Netherlands.
  • 2 Department of Clinical Sciences , Universitá Politecnica delle Marche , Via Ranieri 65 , 60131 Ancona , Italy.
  • 3 Synsight , Genopole Entreprises , 4 Rue Pierre Fontaine , 91000 Évry , France.
  • 4 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.
PMID: 31265285 DOI: 10.1021/acs.jmedchem.9b00413
Abstract

Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme's active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π-π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral Cancer cell line.

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