Emerging opportunities for nicotinamide N-methyltransferase (NNMT) inhibitor clinical translation.

Nicotinamide N-methyltransferase (NNMT) is an enzyme that helps regulate how cells balance energy and methylation potential; however, its abnormal activation can disrupt this balance, fueling diseases such as diabetes, obesity, fibrosis, and cancer. As a result, small-molecule inhibitors targeting NNMT have been developed to reduce this elevated activity, but insufficient target engagement, reduced bioavailability, and unknown safety profiles have led to limited preclinical success across diseases. Advances in NNMT small-molecule inhibitor development have yielded a number of compounds that address these concerns, resulting in drug-like compounds with high affinities for cellular NNMT and promising safety profiles. In this review, we assess the growing therapeutic potential of NNMT inhibitors by highlighting recent developments in NNMT pathophysiology and inhibitor medicinal chemistry.