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.