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  3. Enhancing nicotinamide N-methyltransferase bisubstrate inhibitor activity through 7-deazaadenosine and linker modifications

Enhancing nicotinamide N-methyltransferase bisubstrate inhibitor activity through 7-deazaadenosine and linker modifications

  • Bioorg Chem. 2024 Feb:143:106963. doi: 10.1016/j.bioorg.2023.106963.
Pengyu Li 1,  Cuicui Xia 2,  Xiangqian Kong 3,  Jiancun Zhang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 2 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China; Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230026, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China. Electronic address: [email protected].
PMID: 38048700 DOI: 10.1016/j.bioorg.2023.106963
Abstract

Nicotinamide N-methyltransferase (NNMT) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to nicotinamide (NAM) and other pyridine-related compounds and is involved in various metabolic processes in the human body. In addition, abnormal expression of NNMT occurs under various pathological conditions such as Cancer, diabetes, metabolic disorders, and neurodegenerative diseases, making it a promising drug target worthy of in-depth research. Small-molecule NNMT inhibitors with high potency and selectivity are necessary chemical tools to test biological hypotheses and potential therapies. In this study, we developed a series of highly active NNMT inhibitors by modifying N7 position of adenine. Among them, compound 3-12 (IC50 = 47.9 ± 0.6 nM) exhibited potent inhibitory activity and also had an excellent selectivity profile over a panel of human methyltransferases. We showed that the N7 position of adenine in the NNMT bisubstrate inhibitor was a modifiable site, thus offering insights into the development of NNMT inhibitors.

Keywords

Adenine modification; Bisubstrate inhibition; Nicotinamide N-methyltransferase; S-adenosylmethionine.

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