Proteolysis-targeting chimeras (PROTACs) are an emerging class of therapeutic agents for anticancer treatments by degrading intracellular proteins via the ubiquitin-proteasome system. However, clinical applications of PROTACs are limited by the undesired normal cell toxicity resulting from off-tissue on-target degradation. To address this, we developed a tumor-selective delivery strategy by conjugating carbohydrate moieties to the ligand of the VHL E3 ubiquitin ligase, which enables targeted degradation of proteins of interest in GLUTs-overexpressing cancer cells. We designed and synthesized two series of carbohydrate and BRD PROTAC (ARV-771) conjugates. These compounds degraded BRD4 in a concentration- and time-dependent manner, with NG-2 showing the highest degradation efficiency. Moreover, NG-2's degradation effect was GLUTs- and proteasome-dependent, with selective targeting and effective degradation in high GLUTs-expressing cells. Furthermore, NG-2 inhibited tumor growth without significant toxicity in vivo. These findings demonstrate the potential of carbohydrate-PROTAC as a targeted cancer therapy with minimized off-tissue on-target degradation.
Gao et al. (Fri,) studied this question.