NQO1激活笼锁PROTAC用于细胞特异性降解HDAC6

Proteolysis targeting chimeras (PROTACs) have shifted the paradigms for drug development via target protein degradation. However, PROTACs may exhibit systemic toxicity to normal cells due to indiscriminate degradation and the utility of inhibitors as warhead for protein targeting. Here we propose a new strategy of developing activatable PROTACs for cell-specific degradation of histone deacetylase 6 (HDAC6) with minimal side effects via caging the warhead. Molecular docking reveals that the hydroxyl group of the HDAC6 inhibitor is crucial for targeting. An enzyme-activatable PROTAC is designed by caging the hydroxyl group with the substrate for NAD(P)H: quinone oxidoreductase 1 (NQO1) overexpressed in cancer cells. We demonstrate that the caged PROTAC can be converted to its active form in response to NQO1. The enzyme-activatable PROTAC allows efficient and specific degradation of HDAC6 and exerts antiproliferative activity in NQO1-positive cells. The strategy of caging the ligand for target proteins would afford a new dimension for developing activatable PROTACs with high specificity and minimal side effects.