Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

Chenxia Gao; Wenpeng Hu; Feng Xu; Yuxi Lin; Jiashu Chen; Dayong Shi; Pan Xing; Jiqiang Zhu; Xiangqian Li

doi:10.1016/j.ejmech.2024.117053

Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

Eur J Med Chem. 2024 Nov 13:282:117053. doi: 10.1016/j.ejmech.2024.117053. Online ahead of print.

Authors

Chenxia Gao¹, Wenpeng Hu¹, Feng Xu², Yuxi Lin¹, Jiashu Chen¹, Dayong Shi³, Pan Xing¹, Jiqiang Zhu⁴, Xiangqian Li⁵

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.