PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 μM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC₅₀ values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC_0–2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

中文翻译：

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发现靶向 PTP1B 的选择性蛋白水解嵌合降解剂作为长期降血糖药

PTP1B 是 2 型糖尿病治疗中胰岛素增敏剂的一个有前景的靶标，可以使用蛋白水解靶向嵌合体 (PROTAC) 有效降解。这种方法为长效抗糖尿病药物提供了潜力。我们报告了通过 E3 泛素连接酶 cereblon 靶向 PTP1B 的有效双功能 PROTAC。蛋白质印迹分析显示，48 小时后，浓度从 5 nM 到 5 μM 的 PROTAC 会显着降解 PTP1B。对五种高效 PROTAC 的评估表明，化合物75具有较长的 PEG 连接体（23 个原子），在 48 小时和 72 小时后表现出显着的降解活性，DC ₅₀值分别为 250 nM 和 50 nM。化合物75诱导 PTP1B 选择性降解，需要以泛素化和蛋白酶体依赖性方式与靶蛋白和 CRBN E3 连接酶结合。在口服葡萄糖耐量试验中，它可显着降低_{0-2 小时}血糖 AUC至 29%，并激活 HepG2 细胞中的 IRS-1/PI3K/Akt 信号通路，显示出长期抗糖尿病治疗的前景。