Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase

J Med Chem. 2019 Dec 12;62(23):10783-10797. doi: 10.1021/acs.jmedchem.9b01255. Epub 2019 Dec 3.

Abstract

Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor S-adenosylmethionine 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 cocrystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using the propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Drug Design
  • HCT116 Cells
  • Humans
  • Nicotinamide N-Methyltransferase / antagonists & inhibitors*
  • Nicotinamide N-Methyltransferase / metabolism
  • Permeability
  • Protein Binding

Substances

  • NNMT protein, human
  • Nicotinamide N-Methyltransferase