| Autor: |
Iyamu ID; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States., Zhao T; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States., Huang R; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States. |
| Abstrakt: |
Nicotinamide N -methyltransferase (NNMT) is a metabolic enzyme implicated in multiple diseases, making it a promising therapeutic target. Building upon our recently reported NNMT inhibitor II399 , we systematically investigate the structure-activity relationship by designing and synthesizing a series of analogues. Among them, two top inhibitors II559 ( K i = 1.2 nM) and II802 ( K i = 1.6 nM) displayed over 5000-fold selectivity for NNMT over closely related methyltransferases. Moreover, II559 and II802 showed enhanced cellular inhibition, with a cellular IC 50 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 50 value of ∼10 μM and suppressed the migration of aggressive clear cell renal cancer cell carcinoma cell lines. Overall, II559 and II802 would serve as valuable probes to investigate the enzymatic function of NNMT in health and diseases. |
