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.