Nicotinamide N-methyl transferase (NNMT): An emerging therapeutic target

•Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3).•Interest in NNMT as a therapeutic target has grown significantly in recent years.•NNMT overexpression is linked to cancer, metabolic disorders, and neurodegeneration.•Progress has been made in developing potent and selective NNMT inhibitors.•Most NNMT inhibitors described to date display limited in vivo activity. Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (NA) to generate 1-methyl nicotinamide. Since its discovery 70 years ago, the appreciation of the role of NNMT in human health has evolved from serving only metabolic functions to also being a driving force in diseases, including a variety of cancers. Despite the increasing evidence indicating NNMT as a viable therapeutic target, the development of cell-active inhibitors against this enzyme is lacking. In this review, we provide an overview of the current status of NNMT inhibitor development, relevant in vitro and in vivo studies, and a discussion of the challenges faced in the development of NNMT inhibitors.