JBSNF-000088
(Synonyms: 6-甲氧基-3-吡啶羧胺,6-Methoxynicotinamide) 目录号 : GC38012An inhibitor of NNMT
Cas No.:7150-23-4
Sample solution is provided at 25 µL, 10mM.
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JBSNF-000088 is an inhibitor of nicotinamide N-methyltransferase (NNMT; IC50s = 1.8, 2.8, and 5 ?M for human, monkey, and mouse NNMT, respectively).1 It inhibits NNMT and reduces 1-methyl-nicotinamide (MNA) levels in U2OS and 3T3L1 cells (IC50s = 1.6 and 6.3 ?M, respectively). JBSNF-000088 (50 mg/kg) reduces visceral white adipose tissue (WAT) MNA levels, body weight, fed blood glucose levels, and plasma and liver triglyceride levels, and improves oral glucose tolerance in a mouse model of diet-induced obesity (DIO). It also improves glucose tolerance, without affecting body weight, in the ob/ob and db/db mouse models of insulin resistance and diabetes, respectively.
1.Kannt, A., Rajagopal, S., Kadnur, S.K., et al.A small molecule inhibitor of nicotinamide N-methyltransferase for the treatment of metabolic disordersSci. Rep.8(1)3660(2018)
Cas No. | 7150-23-4 | SDF | |
别名 | 6-甲氧基-3-吡啶羧胺,6-Methoxynicotinamide | ||
Canonical SMILES | COc1ccc(cn1)C(=O)N | ||
分子式 | C7H8N2O2 | 分子量 | 152.15 |
溶解度 | DMSO: ≥ 100 mg/mL (657.25 mM); Water: 1 mg/mL (6.57 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 6.5725 mL | 32.8623 mL | 65.7246 mL |
5 mM | 1.3145 mL | 6.5725 mL | 13.1449 mL |
10 mM | 0.6572 mL | 3.2862 mL | 6.5725 mL |
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2.
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A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders
Sci Rep 2018 Feb 26;8(1):3660.PMID:29483571DOI:10.1038/s41598-018-22081-7.
Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.
Nicotinamide N -methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma
Hepatology 2023 Jan 13.PMID:36633260DOI:10.1097/HEP.0000000000000028.
Background and aims: Nicotinamide N -methyltransferase (NNMT), an enzyme responsible for the methylation of nicotinamide, is involved in many metabolic pathways in adipose tissue and the liver. However, the role of NNMT in editing the tumor immune microenvironment is not well understood. Approach and results: Here, we identified that NNMT can promote IL6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by decreasing the tri-methyl-histone H3 levels on the promoters of IL6 and CSF2 (encoding GM-CSF) and CCAAT/Enhancer Binding Protein, an essential transcription factor for IL6 expression, thus promoting differentiation of macrophages into M2 type tumor-associated macrophages and generation of myeloid-derived suppressor cells from peripheral blood mononuclear cells. Treatment of xenografted tumor models overexpressing NNMT gallbladder carcinoma (GBC) cells with the NNMT inhibitor JBSNF-000088 resulted in compromised tumor development and decreased expression levels of IL6, GM-CSF, tumor-associated macrophage marker CD206, and myeloid-derived suppressor cell marker CD33 but increased expression levels of CD8. In addition, elevated expression of NNMT in tumors of patients with GBC was correlated with increased expression levels of CD206 and CD33 but with decreased levels of CD8 and survival of patients. Conclusions: These data highlight the critical role of NNMT in GBC progression. Inhibition of NNMT by JBSNF-000088 is a potential molecular target for GBC immunotherapy.