ArticleScientific reports2022
Novel tricyclic small molecule inhibitors of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer's disease.Alzheimer's research & therapy · 2025Trial
- NNMT enhances hyperandrogenism in polyendocrine metabolic ovarian syndrome through epigenetic remodelling.Nature metabolism · 2026Article
- Review
- NAD + in fatty liver disease: mechanistic insights and associated targets.Cell biology and toxicology · 2025Review
- Nicotinamide N-Methyltransferase in Cardiovascular Diseases: Metabolic Regulator and Emerging Therapeutic Target.Biomolecules · 2025Review
- SIRT1-Mediated Redox and Senescence Regulation in Cancer: Mechanisms and Therapeutic Implications.Antioxidants (Basel, Switzerland) · 2025Review
- The role of NADnpj metabolic health and disease · 2025Review
- Nicotinamide N-Methyltransferase (NNMT) and Liver Cancer: From Metabolic Networks to Therapeutic Targets.Biomolecules · 2025Review
- Nicotinamide N-Methyltransferase in the Inflammatory Pathogenesis of Graves' Orbitopathy.Investigative ophthalmology & visual science · 2025Article
- Exploring NNMT: from metabolic pathways to therapeutic targets.Archives of pharmacal research · 2024Review
- Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.Diabetes, obesity & metabolism · 2024Article
- Metabolic Signaling in Cancer Metastasis.Cancer discovery · 2024Review
- The Role of NADPharmaceuticals (Basel, Switzerland) · 2024Review
- Review
- It Takes Two to Tango: The Interplay between Prostate Cancer and Its Microenvironment from an Epigenetic Perspective.Cancers · 2024Review
- Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome.Frontiers in pharmacology · 2024Review
- Epigenetic Regulation in Oral Squamous Cell Carcinoma Microenvironment: A Comprehensive Review.Cancers · 2023Review
- Epigenetic Modulators as Therapeutic Agents in Cancer.International journal of molecular sciences · 2023Review
- NADAntioxidants (Basel, Switzerland) · 2023Review
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Authors and funding
28 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator that catalyzes the methylation of nicotinamide (Nam) using the co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (MNA). Overexpression of NNMT and the presence of the active metabolite MNA is associated with a number of diseases including metabolic disorders. We conducted a high-throughput screening campaign that led to the identification of a tricyclic core as a potential NNMT small molecule inhibitor series. Elaborate medicinal chemistry efforts were undertaken and hundreds of analogs were synthesized to understand the structure activity relationship and structure property relationship of this tricyclic series. A lead molecule, JBSNF-000028, was identified that inhibits human and mouse NNMT activity, reduces MNA levels in mouse plasma, liver and adipose tissue, and drives insulin sensitization, glucose modulation and body weight reduction in a diet-induced obese mouse model of diabetes. The co-crystal structure showed that JBSNF-000028 binds below a hairpin structural motif at the nicotinamide pocket and stacks between Tyr-204 (from Hairpin) and Leu-164 (from central domain). JBSNF-000028 was inactive against a broad panel of targets related to metabolism and safety. Interestingly, the improvement in glucose tolerance upon treatment with JBSNF-000028 was also observed in NNMT knockout mice with diet-induced obesity, pointing towards the glucose-normalizing effect that may go beyond NNMT inhibition. JBSNF-000028 can be a potential therapeutic option for metabolic disorders and developmental studies are warranted.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.