2. Academic Validation
  3. Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

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

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: lixiangqian@sdu.edu.cn.
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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