Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme. Specifically, NNMT is involved in controlling methylation potential and influencing epigenetic modification of DNA and histones. Specifically, it uses the universal methyl donor S-adenosylmethionine (SAM) to catalyze the methylation of nicotinamide (NAM). It can directly balance single carbon metabolism with cell methylation and nicotinamide adenine dinucleotide (NAD+) level. Besides, NNMT plays a beneficial role by regulating lipid parameters in the liver. Knockdown of NNMT significantly reduced tumorigenesis and chemical resistance.

Moreover, NNMT is becoming a key intersection between cell metabolism and epigenetic gene regulation. Upregulation of NNMT is in a variety of cancers. Furthermore, the increased expression of NNMT is relevant to tumor progression, metastasis, and worse clinical outcomes. Therefore, NNMT represents an attractive drug target for tumors and other diseases with metabolic disorders and inappropriate protein activation. Now, we will introduce an orally active nicotinamide N-methyltransferase (NNMT) inhibitor, JBSNF-000028.

JBSNF-000028 is an Orally Active NNMT Inhibitor, with Anti-obesity Activity.

From: Neelakantan H, et al. Biochem Pharmacol. 2019 May;163:481-492.

Above all, JBSNF-000028 has IC₅₀s of 0.033 µM, 0.19 µM and 0.21 µM against human NNMT (hNNMT), monkey NNMT (mkNNMT), and mouse NNMT (mNNMT), respectively. Importantly, JBSNF-000028 can be used for the research of metabolic disorders.

Next in importance, JBSNF-000028 inhibits NNMT activity with an EC₅₀ of 2.5 µM in U2OS cells. Particularly, JBSNF-000028 has no cytotoxicity against HepG2 cells. JBSNF-000028 binds below a hairpin structural motif at the nicotinamide pocket and stacks between Tyr-204 and Leu-164. Obviously, JBSNF-000028 is inactive against a broad panel of targets related to metabolism and safety.

JBSNF-000028 with 50 mg/kg by p.o. twice daily for 27 days improves glucose and lipid handling in mice with diet-induced obesity (DIO). Additionally, JBSNF-000028 improves glucose tolerance in NNMT knockout mice with diet-induced obesity.

All in all, JBSNF-000028 is an orally active NNMT inhibitor.

References:

Ruf S, et al. Sci Rep. 2022 Sep 14;12(1):15440.