Discovery of Potent <i>o</i> -Aminobenzoamide-Based NAMPT Inhibitors for Targeting NAPRT-Deficient Gastric Cancer

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ salvage synthesis, represents an attractive target for gastric cancer therapy. Loss of nicotinic acid phosphoribosyltransferase (NAPRT) has been associated with an increased vulnerability to NAMPT inhibition in specific metabolic contexts. Here, we report the design and synthesis of <i>o</i>-aminobenzamide NAMPT inhibitors, among which compound <b>N16</b> exhibited potent enzymatic selectivity and inhibition (IC₅₀ = 17.4 nM) and pronounced activity against NAPRT-deficient HGC-27 cells (IC₅₀ = 1.3 nM). <b>N16</b> depleted NAD⁺ and ATP, disrupted mitochondrial potential, and suppressed self-renewal, proliferation, invasion, and migration while inducing cell-cycle arrest and apoptosis. Compared with lead compound <b>1</b>, <b>N16</b> displayed improved pharmacokinetics and <i>in vivo</i> antitumor efficacy. Notably, nicotinic acid coadministration enhanced tolerability without compromising antitumor activity <i>in vivo</i>. Collectively, these findings identify <b>N16</b> as a promising NAMPT inhibitor with translational potential for treating metabolically vulnerable gastric cancer, particularly NAPRT-deficient subtypes.