Discovery of Potent o-Aminobenzoamide-Based NAMPT Inhibitors for Targeting NAPRT-Deficient Gastric Cancer

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for NAD+ synthesis and a therapeutic target in gastric cancer.
• Loss of nicotinic acid phosphoribosyltransferase (NAPRT) creates metabolic vulnerabilities exploitable by NAMPT inhibitors.

Purpose of the Study:

• To design and synthesize novel NAMPT inhibitors.
• To evaluate the efficacy of these inhibitors, particularly compound N16, in gastric cancer models, especially those deficient in NAPRT.

Main Methods:

• Synthesis of o-aminobenzamide NAMPT inhibitors.
• Enzymatic assays to determine IC50 values for NAMPT inhibition.
• Cell-based assays to assess N16's effects on NAD+, ATP, mitochondrial potential, cell cycle, apoptosis, proliferation, invasion, and migration.
• Pharmacokinetic studies and in vivo antitumor efficacy assessments.
• Evaluation of nicotinic acid coadministration for tolerability.

Main Results:

• Compound N16 demonstrated potent and selective NAMPT inhibition (IC50 = 17.4 nM).
• N16 showed significant activity against NAPRT-deficient HGC-27 cells (IC50 = 1.3 nM), depleting NAD+ and ATP, disrupting mitochondrial potential, and inducing apoptosis.
• N16 exhibited improved pharmacokinetics and in vivo antitumor efficacy compared to a lead compound.
• Nicotinic acid coadministration improved tolerability without reducing antitumor effects.

Conclusions:

• N16 is a potent NAMPT inhibitor with significant preclinical efficacy.
• N16 shows translational potential for treating gastric cancer, especially NAPRT-deficient subtypes.
• The findings support N16 as a promising therapeutic candidate for gastric cancer treatment.