Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

  • Eur J Med Chem. 2025 Jan 15:282:117053. doi: 10.1016/j.ejmech.2024.117053.
Chenxia Gao  1 ,  Wenpeng Hu  1 ,  Feng Xu  2 ,  Yuxi Lin  1 ,  Jiashu Chen  1 ,  Dayong Shi  3 ,  Pan Xing  1 ,  Jiqiang Zhu  4 ,  Xiangqian Li  5
Affiliations
  • 1. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
  • 2. The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, PR China.
  • 3. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, Shandong, PR China.
  • 4. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China; Shandong Linghai Biotechnology Co., Ltd, Jinan, 250299, Shandong, PR China.
  • 5. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, Shandong, PR China. Electronic address: [email protected].
PMID: 39561499 DOI: 10.1016/j.ejmech.2024.117053
Abstract

Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC50 value of 1.061 ± 0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates Insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.

Keywords
Allosteric inhibitors; BB site; Bromocatechol-chalcone; PTP1B; Type 2 diabetes mellitus.
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