The PROTACtable genome: a systematic assessment of drug target tractability

Experimental Science Jul 21, 2021

An Open Targets project bringing together researchers from the European Bioinformatics Institute (EMBL-EBI), the Wellcome Sanger Institute, GlaxoSmithKline, Sanofi-Aventis, and Bristol Myers Squibb has established a new framework to assess whether human proteins could be targeted with Proteolysis Targeting Chimeras (PROTACs).

The research was published in the journal Nature Reviews Drug Discovery.

Exploiting a cell’s machinery

PROTACs are a new class of drugs that exploit a cell’s own machinery to remove specific disease-related proteins.

“Accelerated protein degradation could be an effective way to treat disease and probe biology, and this concept has been gaining increased attention over the past few years both in industry and academia,” explains Andrew Leach, Head of Industry Partnerships and Head of Chemical Biology at EMBL-EBI.

“The discovery and development of molecular degraders in general and PROTACs in particular as new drug modalities makes this a natural and timely topic for us to consider as part of Open Targets,” added Melanie Schneider, a protein computational scientist in the Leach team, who led the research.

“PROTACtable” proteins

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 an inbuilt machinery to destroy proteins that have outlived their function, first tagging proteins for destruction by attaching ubiquitin molecules. The ubiquitin tag is then recognised and the tagged protein destroyed by the cell’s proteasome. PROTACs are designed to accelerate this process for specific proteins, and could be applied to 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 GlaxoSmithKline, subsequently expanded and now integrated in the Open Targets Platform. Using publicly available data sources, it assesses whether a protein could be targeted using a PROTAC based on its sequence, its location and natural turnover rate in the cell, and published literature evidence. The framework will help drug discovery scientists to gauge the PROTACtability of their protein of interest, and prioritise their research accordingly.

“The interpretation of experimental data is not always straightforward and may vary depending on a given project at hand,” explain Leach and 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 currently working on integrating this framework into the Platform, where it will complement the existing protein tractability assessments. On the subject of future plans for their research, Schneider 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.”

Citation

Schneider, M., Radoux, C.J., Hercules, A. et al. The PROTACtable genome. Nat Rev Drug Discov (2021). https://doi.org/10.1038/s41573-021-00245-x

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