Though a growing number of PROTACs have been developed, including a handful currently in clinical trials, there hasn’t been a systematic assessment of which proteins could be targeted using this approach.
Cells have inbuilt machinery to destroy proteins that have outlived their usefulness. This involves tagging proteins for destruction by attaching a small protein called ubiquitin. The ubiquitin tag is then recognised and the tagged protein is destroyed.
PROTACs are designed to accelerate this process for specific proteins, and could be applied to treat a wide variety of diseases. Using their workflow, the team analysed the entire human proteome and identified over 1,000 “PROTACtable” proteins, many of which are not currently targeted by other types of therapeutics.
Integration into the Open Targets Platform
The team’s workflow is based on a method developed by a group at GSK, subsequently expanded and now integrated into the Open Targets Platform. Using publicly available data sources, the new method assesses whether a protein could be targeted using a PROTAC, based on the protein’s sequence, location, natural turnover rate in the cell, and evidence from published literature. The framework will help drug discovery researchers to gauge the PROTACtability of their protein of interest, and to prioritise their research accordingly.
“The interpretation of experimental data is not always straightforward, and may vary depending on a given project at hand,” explains Schneider. “Thus we aimed to provide as much data as possible, with clear guidance on how to use and interpret this information – leaving room for users to adapt our work and data to their specific project aims.”
The Open Targets Platform data team is working to integrate this framework into the platform, where it will complement the existing protein tractability assessments. On the subject of future plans for their research, Andrew comments: “PROTACs – and degraders in general – are rapidly developing and so an obvious next step will be to refine and update the pipeline as more data becomes available on PROTACs as a drug modality.”