Structure-Activity Relationship Studies on Cell-Potent Nicotinamide -Methyltransferase Bisubstrate Inhibitors.

Nicotinamide -methyltransferase (NNMT) is a metabolic enzyme implicated in multiple diseases, making it a promising therapeutic target. Building upon our recently reported NNMT inhibitor , we systematically investigate the structure-activity relationship by designing and synthesizing a series of analogues. Among them, two top inhibitors ( = 1.2 nM) and ( = 1.6 nM) displayed over 5000-fold selectivity for NNMT over closely related methyltransferases. Moreover, and showed enhanced cellular inhibition, with a cellular IC value of approximately 150 nM, making them the most cell-potent bisubstrate inhibitors reported to date. Furthermore, both inhibitors reduced the cell viability with a GI value of ∼10 μM and suppressed the migration of aggressive clear cell renal cancer cell carcinoma cell lines. Overall, and would serve as valuable probes to investigate the enzymatic function of NNMT in health and diseases.