JBSNF-000088

JBSNF-000088 is the research code for 6-methoxynicotinamide. It was selected from a screening campaign for inhibitors of NNMT, an enzyme that methylates nicotinamide [1]. JBSNF-000028 is a different, later tricyclic inhibitor from the same programme; its results and safety assays should not be attributed to JBSNF-000088 [2].

Metabolic study. Mice made obese by a high-fat diet received 50 mg/kg by mouth twice daily for 30 days. They gained less weight than vehicle controls despite similar food intake. Their oral glucose tolerance, fasting insulin and HOMA-IR improved, and plasma and liver triglycerides fell [1]. The study did not include a weight-matched control, so improved glucose handling may have followed the difference in body weight [1].

Less responsive models. The same regimen did not reduce weight in ob/ob or db/db mice. Glucose tolerance improved in ob/ob mice, but not significantly in db/db mice; the db/db group also had no HOMA-IR improvement [1]. In high-fat-fed NNMT-knockout mice the compound gave no further glucose benefit, supporting an NNMT-dependent effect in that experiment. The knockout experiment produced relatively little obesity or glucose intolerance, which limits how much it can establish [1].

Other experimental work. In a small mouse model of endometriosis, five oral doses reduced the number and weight of lesions [3]. Gallbladder-cancer xenografts showed less tumor development after treatment [4]. In lung-cancer cells resistant to an EGFR inhibitor, JBSNF-000088 enhanced the inhibitor's effect in culture; it did not inhibit growth of non-resistant cells by itself [5]. These are exploratory models, not evidence that the compound treats any of these conditions in people.

NNMT transfers a methyl group from S-adenosylmethionine to nicotinamide, producing 1-methylnicotinamide (MNA) [1]. JBSNF-000088 is a nicotinamide-like molecule that competes at NNMT's substrate site. It inhibited purified human, monkey and mouse NNMT at 1.8, 2.8 and 5.0 µM, respectively. Human and mouse cell assays showed reduced MNA production at micromolar concentrations [1].

Crystal structures contained the N-methylated form of JBSNF-000088 bound to NNMT. That product was also detected at low levels in treated mouse plasma, but it inhibited NNMT poorly. The authors therefore proposed that the parent compound is a slowly converted substrate analog [1]. A single oral dose lowered plasma MNA for up to four hours in mice [1]. This work did not show that JBSNF-000088 raises tissue NAD+ in humans.

Human adverse effects and long-term safety have not been measured. The 2018 study described four weeks of 50 mg/kg twice-daily oral treatment as well tolerated in mice, without a food-intake change [1]. In laboratory tests the compound was negative in Ames and micronucleus assays, did not reduce HepG2 cell viability at up to 100 µM, and showed no activity in a 34-target screen at 10 µM [1]. These screens do not establish safety in people or exclude interactions at clinical exposures, which have never been defined.