1. Academic Validation
  2. Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents

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

  • J Med Chem. 2024 May 9;67(9):7569-7584. doi: 10.1021/acs.jmedchem.4c00356.
Zunhua Yang 1 Yuqi Ying 1 Shaobing Cheng 2 Jiamin Wu 2 Ziwei Zhang 1 Pei Hu 3 Jian Xiong 1 Huilan Li 2 Qing Zeng 1 Zhifang Cai 1 Yulin Feng 2 Yuanying Fang 2
Affiliations

Affiliations

  • 1 College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
  • 2 National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Chinese Medicine, Nanchang 330006, China.
  • 3 Jiangzhong Pharmaceutical Co., Ltd., Nanchang 330103, China.
Abstract

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.

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