Back to Search
Start Over
Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 May 09; Vol. 67 (9), pp. 7569-7584. Date of Electronic Publication: 2024 May 01. - Publication Year :
- 2024
-
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 DC <subscript>50</subscript> 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 <subscript>0-2h</subscript> 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.
- Subjects :
- Animals
Humans
Mice
Adaptor Proteins, Signal Transducing metabolism
Drug Discovery
Hep G2 Cells
Signal Transduction drug effects
Ubiquitin-Protein Ligases metabolism
Hypoglycemic Agents pharmacology
Hypoglycemic Agents chemistry
Hypoglycemic Agents chemical synthesis
Protein Tyrosine Phosphatase, Non-Receptor Type 1 metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 1 antagonists & inhibitors
Proteolysis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38690687
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00356