Exploring Unconventional SAM Analogues To Build Cell‐Potent Bisubstrate Inhibitors for Nicotinamide N‐Methyltransferase

• Published in: Angewandte Chemie International Edition Vol. 61; no. 16; pp. e202114813 - n/a
• Main Authors: Iyamu, Iredia D., Vilseck, Jonah Z., Yadav, Ravi, Noinaj, Nicholas, Huang, Rong
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 11.04.2022; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Binding; Bisubstrate Analogues; Bisubstrate Inhibitors; Cell-Potent Inhibitors; Chemistry; Chemistry, Multidisciplinary; Computer applications; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Inhibitors; Methyltransferase; Methyltransferases - metabolism; Niacinamide - pharmacology; Nicotinamide; Nicotinamide N-Methyltransferase - chemistry; Nicotinamide N-Methyltransferase - metabolism; Physical Sciences; SAM Analogues; Science & Technology; Substrates; Enzymes; Bisubstrate Inhibitors; Bisubstrate Analogues; Cell-Potent Inhibitors; EXPRESSION; SAM Analogues
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202114813

Nicotinamide N‐methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell‐potent NNMT bisubstrate inhibitor II399, demonstrating a Ki of 5.9 nM in a biochemical assay and a cellular IC50 value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399′s low nM binding affinity. Notably, II399 is 1 000‐fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell‐potent inhibitors for other SAM‐dependent methyltransferases. The first cell‐potent and selective nicotinamide N‐methyltransferase (NNMT) bisubstrate inhibitor, II399, was discovered by structure‐based optimization by introducing unconventional S‐adenosyl‐L‐methionine (SAM) mimics. The inhibition mechanism studies and crystal structure of the NNMT–II399 complex confirm its engagement with both SAM and substrate binding sites. II399 potently inhibits the methyltransferase activity of NNMT in cells.