2. Academic Validation
  3. NAMPT-targeted para-ureidobenzylamine derivatives: Design, synthesis, and antitumor evaluation in gastrointestinal cancers

NAMPT-targeted para-ureidobenzylamine derivatives: Design, synthesis, and antitumor evaluation in gastrointestinal cancers

  • Eur J Med Chem. 2026 Apr 15:308:118699. doi: 10.1016/j.ejmech.2026.118699.
Huiqian Peng 1,  Lejing Zhu 1,  Lixian Shen 1,  Zhen Li 1,  Yiting Shi 1,  Rifan Ding 1,  Tao Zhang 1,  Chengxuan Hu 1,  Jie He 1,  Zhen Wang 2,  Weifan Jiang 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, 410008, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, 810008, China. Electronic address: [email protected].
  • 3 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
PMID: 41722430 DOI: 10.1016/j.ejmech.2026.118699
Abstract

Gastrointestinal cancers remain a major clinical challenge, underscoring the need for innovative therapeutic strategies. Given the elevated NAMPT expression in these malignancies, we designed and synthesized a series of 29 small-molecule NAMPT inhibitors derived from lead compound 9a. Among them, Q24 exhibited the strongest activity, showing nanomolar inhibition of NAMPT and subnanomolar antiproliferative effects against HGC-27 cells. Molecular docking and molecular dynamics simulation supported its strong binding to NAMPT. A comprehensive set of in vitro studies demonstrated that Q24 consistently surpassed 9a in suppressing proliferation and migration, disrupting energy metabolism, arresting the cell cycle, and inducing Apoptosis. Q24 also displayed favorable oral pharmacokinetic properties and good systemic tolerability. In xenograft models, Q24 significantly inhibited tumor growth, achieving a tumor growth inhibition rate of 68.9% without notable histopathological abnormalities. These findings establish NAMPT as a promising therapeutic target and identify Q24 as a compelling lead for the development of Anticancer drugs.

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