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

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Yongzhi Gao, Matthijs J. Van Haren, Ned Buijs, Paolo Innocenti, Yurui Zhang, Davide Sartini, Roberto Campagna, Monica Emanuelli, Richard B. Parsons, Willem Jespers, Hugo Gutiérrez-De-Terán, Gerard J.P. Van Westen, Nathaniel I. Martin

Original languageEnglish
Pages (from-to)12938-12963
Number of pages26
JournalJournal of Medicinal Chemistry
Issue number17
Accepted/In press2021
Published9 Sep 2021

Bibliographical note

Funding Information: Financial support was provided by the European Research Council (ERC consolidator grant to N.I.M, Grant agreement 725523). Publisher Copyright: © 2021 The Authors. Published by American Chemical Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


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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