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.

中文翻译：

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溴儿茶酚-查尔酮衍生物对 PTP1B 的变构抑制


变构抑制剂的开发可能是发现靶向 PTP1B 的降糖药物的可行策略。占据 BB 位点（即疏水口袋）的变构抑制剂以开放构象限制 WPD 环，从而阻止生理性去磷酸化反应。在 BB 位点，设计并合成了 60 种溴邻苯二酚-查尔酮衍生物作为 PTP1B 对抗糖尿病的变构抑制剂。最有效的化合物 LXQ-87 （C8） 非竞争性地抑制 PTP1B，IC50 值为 1.061 ± 0.202 μM。口服 LXQ-87 可降低患有 T2DM 的 BKS db/db 小鼠的空腹血糖水平并改善葡萄糖耐量和血脂异常。LXQ-87 通过直接与细胞内 PTP1B 结合来减轻胰岛素抵抗并促进细胞葡萄糖摄取。