Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents

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 AUC0–2h 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.蛋白酪氨酸磷酸酶1B（PTP1B）是2型糖尿病治疗中胰岛素增敏剂的极具潜力的靶点，可借助蛋白水解靶向嵌合体（proteolysis-targeting chimera, PROTAC）实现有效降解。该策略为长效抗糖尿病药物的研发提供了潜在可能。本研究报道了一类靶向PTP1B的高效双功能PROTAC分子，其通过E3泛素连接酶cereblon介导发挥作用。蛋白质免疫印迹（Western Blot）分析显示，在5 nM至5 μM的浓度范围内，该类PROTAC在处理48小时后可显著降解PTP1B。对5种高活性PROTAC的评估结果表明，带有23个原子长聚乙二醇（PEG）连接子的化合物75表现出优异的降解活性，在48小时和72小时时的降解半数有效浓度（DC50）分别为250 nM和50 nM。化合物75可选择性降解PTP1B，其降解过程依赖于靶蛋白与CRBN E3泛素连接酶的结合，且以泛素化和蛋白酶体依赖的方式进行。在口服葡萄糖耐量试验中，化合物75可将0~2小时血糖曲线下面积（AUC0–2h）显著降低至29%，并可激活HepG2细胞中的IRS-1/PI3K/Akt信号通路，在长效抗糖尿病治疗领域展现出良好的应用前景。