Doxorubicin photochemical probes for unbiased target discovery

Doxorubicin is a widely used and efficient chemotherapeutic for the treatment of solid and hematological cancers. However, doxorubicin can cause serious cardiotoxic side-effects culminating in heart failure. Multiple mechanisms have been proposed for this cardiotoxic effect, though to-date none have led to the development of targeted cardioprotective drugs. This is due to the fact that mechanistic insight into cardiotoxicity stems from model systems that poorly represent human disease, and that no unbiased approach has so far been taken to identify the cellular targets of doxorubicin in the heart.

In this project we will use photo-crosslinkable chemical probes to identify the cellular protein targets of doxorubicin in an unbiased manner. We will first test different chemical probes in a cardiomyocyte cell line for proof-of-concept protein target labelling. We will then apply the probes to target identification in a well-established clinically-relevant rat model of doxorubicin-cardiotoxicity.

Image title: Unbiased profiling of the protein targets of doxorubicin in cardiomyocytes using photo-chemical probes and click chemistry-based analysis