Bioorthogonal sticky-PROTACs for targeted and sustained protein degradation.

Abstract

Proteolysis-targeting chimeras (PROTACs) can catalytically eliminate disease-driving proteins, but nonspecific exposure, rapid clearance, and concentration-dependent hook effects limit their tumor selectivity and durability. Here, we report a kinetically programmed bioorthogonal sticky PROTAC (VPT) that temporally separates tumor capture from prodrug activation. Tetrazine (Tz) handles were selectively installed on HER2-overexpressing tumor cells through antibody-directed metabolic glycoengineering. VPT integrates a trans-cyclooctene (TCO) group for rapid Tz-mediated covalent anchoring with a vinyl ether (VE) cage for slower Tz-triggered release of an active BRD4 degrader. The TCO-Tz ligation proceeded approximately 4890-fold faster than VE-Tz cleavage, enabling rapid tumor-cell retention followed by sustained local activation. In HER2-pretargeted cells, VPT prolonged BRD4 degradation after washout, showed no evident hook effect within the tested concentration range. Bioorthogonal anchoring also maintained tumor-associated fluorescence for up to 120 h. In SKOV3 and BT474 xenografts, HER2-MTz plus VPT achieved tumor growth inhibition rates of 85.8% and 95.7%, respectively, outperforming the corresponding non-sticky control. This dual-kinetics design provides a generalizable strategy for coupling tumor-selective retention with sustained in situ PROTAC activation.

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