Nov 25, 2024

Study Suggests New Ways to Target Cancer-Linked Proteins

Faculty News
Dr. Masoud Vedadi

Scientists led by Drs. Masoud Vedadi and Rima Al-awar from the Department of Pharmacology & Toxicology at the Temerty Faculty of Medicine, University of Toronto, and the Ontario Institute for Cancer Research, have introduced innovative PROTACs (Proteolysis-targeting chimeras) designed to degrade WDR5, a protein implicated in various cancers.

PROTACs are molecules that tag unwanted proteins for degradation via the cell’s natural waste disposal system, leveraging components known as E3 ligases. However, the limited number of effectively utilized E3 ligase substrate receptors has posed challenges, as mutations or reduced expression can diminish PROTAC efficacy.

Addressing this issue, Drs. Vedadi and Al-awar’s teams developed efficient PROTACs presenting WDR5 to DCAF1, a substrate receptor of the certain E3 ligases. They created four new PROTACs capable of degrading WDR5 proteins within cells.

High-resolution crystal structures of the ternary complexes of DCAF1, the PROTACs, and WDR5 revealed that flexible loops of DCAF1 play a critical role in accommodating various PROTAC-WDR5 complexes. This surface plasticity is key to DCAF1’s ability to interact with diverse proteins.

“Our findings shed light on how DCAF1 substrate diversity can be exploited to target proteins previously challenging to degrade,” said Dr. Vedadi. “This opens new avenues for developing targeted cancer therapies by enabling the selective degradation of oncogenic proteins like WDR5 more efficiently.”

The study enhances our understanding of protein degradation pathways and offers new promise for designing more effective treatments for cancers that have been difficult to treat.

Reference: Researchers develop DCAF1-based PROTACs for targeted cancer therapy