2. Academic Validation
  3. Discovery of Potent o-Aminobenzoamide-Based NAMPT Inhibitors for Targeting NAPRT-Deficient Gastric Cancer

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

  • J Med Chem. 2026 Feb 12;69(3):2625-2646. doi: 10.1021/acs.jmedchem.5c02564.
Heng Yang 1 2,  Zhiyi Li 1,  Huiqian Peng 1,  Lixian Shen 1 3,  Zhen Li 1,  Lejing Zhu 1,  Rifan Ding 1,  Yiting Shi 1,  Yuting Liu 1,  Miao Zhang 1,  Linsheng Zhuo 1,  Meiling Yang 4,  Zhen Wang 1 3 5 6,  Weifan Jiang 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 2 Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 3 School of Basic Medicine, The First Affiliated Hospital, The Second Affiliated Hospital, MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 4 Department of Oncology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, China.
  • 5 Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai 810008, China.
  • 6 National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.
PMID: 41592801 DOI: 10.1021/acs.jmedchem.5c02564
Abstract

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.

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