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 PDE{delta} in different types of cells. We also confirmed the direct binding interaction of PDE{delta} with sorafenib by CETSA and SPR assays. Together, our research suggests that PDE{delta} is a new potential target of sorafenib, and PROTAC technology may be a promising approach for cellular target identification of bioactive compounds of interest.