Identification of PDE6D as a potential target of sorafenib via PROTAC technology

Abstract The identification of unknown target of a multi-kinase inhibitor sorafenib is important to better understand the mechanism of action of this drug in anti-cancer and anti-fibrotic treatments. Here, we report the combination of PROTAC technique with quantitative proteomic analysis to identify the unknown cellular targets of sorafenib. Sorafenib-based PROTAC can strongly degrade a non-kinase target PDEδ in different types of cells. We also confirmed the direct binding interaction of PDEδ with sorafenib by CETSA and SPR assays. Together, our research suggests that PDEδ is a new potential target of sorafenib, and PROTAC technology may be a promising approach for cellular target identification of bioactive compounds of interest.