Discovery of Potent o -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 o-aminobenzamide NAMPT inhibitors, among which compound N16 exhibited potent enzymatic selectivity and inhibition (IC₅₀ = 17.4 nM) and pronounced activity against NAPRT-deficient HGC-27 cells (IC₅₀ = 1.3 nM). N16 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 1, N16 displayed improved pharmacokinetics and in vivo antitumor efficacy. Notably, nicotinic acid coadministration enhanced tolerability without compromising antitumor activity in vivo. Collectively, these findings identify N16 as a promising NAMPT inhibitor with translational potential for treating metabolically vulnerable gastric cancer, particularly NAPRT-deficient subtypes.