Cancer Selective Target Degradation by Folate-Caged PROTACs

PROTACs (proteolysis targeting chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to the off-tissue on-target degradation effect limits their clinical applications. Precise control of a PROTAC's on-target degradation activity in a tissue-selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to a ligand of the VHL E3 ubiquitin ligase, to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus noncancerous normal cells. We show that our folate-PROTACs, including BRD PROTAC (folate-ARV-771), MEK PROTAC (folate-MS432), and ALK PROTAC (folate-MS99), are capable of degrading BRDs, MEKs, and ALK, respectively, in a folate receptor-dependent manner in cancer cells. This design provides a generalizable platform for PROTACs to achieve selective degradation of POIs in cancer cells.

Automated summary

PROTACs are emerging as a promising therapeutic modality for degrading intracellular protein targets, but potential toxicity in normal cells limits their applications. By conjugating a folate group to a ligand of the VHL E3 ubiquitin ligase, a cancer cell selective delivery strategy for PROTACs was developed to achieve targeted degradation of proteins of interest in cancer cells. Folate-PROTACs provide a platform for selective degradation of proteins of interest in cancer cells.