Development of Potent and Selective Nicotinamide N-methyltransferase Inhibitors for Kidney Cancer

Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that regulates energy balance and methylation potential through the methylation of nicotinamide using S-adenosylmethionine (SAM) as the cofactor. NNMT has emerged as a novel target for both primary and metastatic ccRCC, as its high expression in ccRCC tumor tissues is linked with low survival. Meanwhile, NNMT depletion or inhibition efficiently suppresses the growth and metastasis of ccRCC in cellular and animal studies. Here, we report rational design and synthesize cell-potent and selective NNMT inhibitors with cellular IC50 values of 140 nM, representing the most cell-potent inhibitors to date. Furthermore, our NNMT inhibitors suppress renal cancer 786O and Caki-1 cell growth with a GI50 value of 9.3 and 7.3 µM, respectively. Moreover, our NNMT inhibitors reduced the migration of renal cancer cells through wound healing assay. In summary, our inhibitors would serve as valuable chemical probes to investigate the catalytical function of NNMT and evaluate the therapeutic potential of NNMT for kidney cancer. Citation Format: Rong Huang, Iredia Iyamu. Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A024.