JBSNF-000088

JBSNF-000088 (6-methoxynicotinamide) is a potent and orally active small molecule inhibitor of nicotinamide N-methyltransferase (NNMT), though commonly marketed in peptide research circles. It demonstrates IC50 values of 1.8 µM, 2.8 µM, and 5.0 µM for human, monkey, and mouse NNMT respectively. In preclinical studies, JBSNF-000088 has shown significant efficacy in reducing body weight, improving insulin sensitivity, normalizing glucose tolerance, and potentially reversing EGFR-TKI resistance in non-small cell lung cancer. The compound functions as a slow-turnover substrate analog that modulates the NAD+ salvage pathway, influencing energy metabolism and sirtuin activity.

Metabolic and Weight Management Effects

JBSNF-000088 demonstrates significant metabolic benefits in preclinical models. In diet-induced obese mice, treatment at 50 mg/kg (bid, oral) caused substantial reduction in body weight, improved insulin sensitivity, and normalized glucose tolerance to levels comparable with lean control mice^[1][2]. The compound reduced visceral white adipose tissue (WAT) methylnicotinamide (MNA) levels, decreased fed blood glucose levels, and lowered both plasma and liver triglyceride levels while improving oral glucose tolerance^[1]. These effects were absent in NNMT knockout mice on high-fat diet, confirming the target specificity of JBSNF-000088^[1].

Cancer Therapy Enhancement

In cancer research, JBSNF-000088 has shown promise in overcoming resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC)^[3]. The combination of JBSNF-000088 and gefitinib synergistically inhibited the growth of EGFR-TKI-resistant PC9/GR and HCC827/GR cells^[3]. In animal studies, combined treatment with gefitinib plus JBSNF-000088 (50 mg/kg per day, intragastric) significantly inhibited tumor growth compared to either agent alone^[3]. Higher NNMT expression levels in EGFR-TKI-resistant NSCLC tissue samples correlated with shorter progression-free survival, making NNMT inhibition a promising strategy^[3].

NAD+ Metabolism and Energy Regulation

JBSNF-000088 modulates cellular energy metabolism through its effects on the NAD+ salvage pathway^[4][5]. By inhibiting NNMT, the compound prevents the methylation of nicotinamide to 1-methylnicotinamide (MNA), thereby preserving nicotinamide for NAD+ biosynthesis^[4][5]. This increases intracellular NAD+ levels and enhances NAD+-dependent SIRT1 activity, leading to improved mitochondrial function and energy expenditure^[4][5]. Treatment achieved approximately 50% reduction in circulating MNA levels in preclinical models^[1].

Pharmacokinetic Profile

The compound exhibits favorable pharmacokinetic properties with rapid oral absorption (Tmax of 0.5 hours) and approximately 40% oral bioavailability in mice^[1]. Upon oral gavage at 10 mg/kg, JBSNF-000088 achieved a Cmax of 3,568 ng/mL with low plasma clearance of 21 mL/min/kg (approximately 25% of hepatic blood flow)^[1]. The volume of distribution at steady state was 0.7 L/kg, roughly equal to total body water in mice^[1]. The compound demonstrated good physico-chemical properties with no liability in hERG and NaV1.5 cardiac safety assays (<30% inhibition at 10 µM)^[2].

Preclinical Safety Profile

JBSNF-000088 has demonstrated an acceptable safety profile in preclinical studies. The compound showed no toxicity at tested concentrations of 10, 30, and 100 µM in 72-hour cell culture studies^[2]. Cardiac safety assessments revealed no liability in hERG and NaV1.5 ion channel assays, with less than 30% inhibition at 10 µM, indicating minimal cardiovascular risk^[2]. The compound was selective against a panel of 34 receptors, channels, and enzymes, suggesting good target specificity^[2].

In Vivo Tolerability

In chronic efficacy studies using diet-induced obesity, ob/ob, and db/db mouse models, JBSNF-000088 was administered at 50 mg/kg twice daily via oral route for up to 4 weeks without observable adverse effects^[1][2]. The compound possessed good physico-chemical and pharmacokinetic properties and did not have any obvious safety or drug-drug interaction liabilities in preclinical assessments^[2].

Limitations and Considerations

Despite the promising preclinical data, several limitations should be noted. JBSNF-000088 exhibits a very short plasma half-life of 0.5 hours upon intravenous administration and 0.4 hours for apparent oral half-life, which may limit its therapeutic duration of action^[1]. The compound has not yet advanced to human clinical trials, so safety data in humans is not available^[6][7]. As with all NNMT inhibitors, the long-term effects of sustained NNMT inhibition on epigenetic regulation and methylation balance remain to be fully characterized^[8].

NNMT Inhibitor Class Considerations

As an NNMT inhibitor, JBSNF-000088 affects fundamental metabolic pathways including SAM/SAH balance and NAD+ metabolism^[4][5][8]. While no significant adverse effects have been reported in preclinical models, the impact on global methylation potential and epigenetic regulation warrants careful monitoring in any future clinical development^[8]. Other NNMT inhibitors in development have completed FDA-regulated toxicology studies, suggesting the class may have acceptable safety characteristics, though individual compound profiles may vary^[9].