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Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics.

Authors
  • Gao, Yongzhi1
  • van Haren, Matthijs J1
  • Buijs, Ned1
  • Innocenti, Paolo1
  • Zhang, Yurui1
  • Sartini, Davide2
  • Campagna, Roberto2
  • Emanuelli, Monica2
  • Parsons, Richard B3
  • Jespers, Willem4, 5
  • Gutiérrez-de-Terán, Hugo5
  • van Westen, Gerard J P4
  • Martin, Nathaniel I1
  • 1 Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands. , (Netherlands)
  • 2 Department of Clinical Sciences, Universitá Politecnica delle Marche, Via Ranieri 65, 60131 Ancona, Italy. , (Italy)
  • 3 Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom. , (United Kingdom)
  • 4 Drug Discovery and Safety, Leiden Academic Center for Drug Research, Einsteinweg 55, 2333 CC Leiden, The Netherlands. , (Netherlands)
  • 5 Department of Cell and Molecular Biology, Uppsala University, Uppsala 75124, Sweden. , (Sweden)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Sep 09, 2021
Volume
64
Issue
17
Pages
12938–12963
Identifiers
DOI: 10.1021/acs.jmedchem.1c01094
PMID: 34424711
Source
Medline
Language
English
License
Unknown

Abstract

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.

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