The HSP90-dependent bioorthogonal PROTAC prodrug system enables tumor-selective and enhanced protein degradation - PubMed
4 hours ago
- #Bioorthogonal Chemistry
- #PROTACs
- #HSP90
- HSP90-dependent bioorthogonal PROTAC prodrug system (HBPROTAC) enables tumor-specific protein degradation.
- HBPROTAC consists of Tz-PU (tetrazine-conjugated HSP90 inhibitor) and TCO-caged PROTAC prodrugs (TCO-MZ1 or TCO-DT2216).
- Active PROTACs are released via inverse electron demand Diels-Alder (IEDDA) reactions between Tz-PU and TCO-caged prodrugs.
- HBPROTAC demonstrated tumor-specific activation and degradation of BRD4 and Bcl-xL proteins.
- Tz-PU inhibition synergistically enhances degradation efficiency through HSP90-mediated signaling.
- Tumor-specific degradation confirmed in various tumor cell lines and melanoma mouse models.
- HBPROTAC reduces off-tissue on-target toxicity, offering a platform for spatiotemporal protein degradation control.