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Despite rapid advances in disease biology, many promising drug targets remain out of reach of traditional drug discovery due to the absence of suitable binding pockets for small molecules. In recent years, covalent compounds have shown great utility in tackling poorly tractable targets, for example those with shallow or ‘cryptic’ binding sites. These compounds are able to recognise and bind irreversibly to targets, often with specificity. Recent advances in chemical proteomics have enabled the measurement of binding interactions for thousands of protein targets simultaneously. Yet, the discovery and optimisation of selective covalent drug molecules remain hampered by challenges of speed, scale and data completeness.

The GSK–Crick team has built a scalable platform technology using label-free, live-cell chemical proteomics to achieve quantification of ligand–protein interactions for covalent libraries on a proteome-wide scale. Modular ‘direct-to-biology’ high-throughput chemistry has been integrated to access drug-like scaffolds with tunable covalent reactivity rapidly and without the need for purification steps. 

This approach has enabled the generation of compound–protein data matrices with exceptionally high data completeness, mapping whole compound libraries against over 8,000 cellular proteins. In this way, an ‘atlas’ of interactions has emerged, which can unlock drug discovery opportunities on an industrially relevant scale. 

Finally, the incorporation of a scalable computational pipeline and interpretable machine learning models has enabled the prediction of which protein fragments (peptides) can be measured and which proteins are likely to be targetable by covalent compounds.

The beauty of the approaches, techniques and reagents used in this work is that they are likely to be readily available to many researchers in academia; in that sense, it is an enabler that can democratise probe and tool discovery, allowing many to explore specific areas of biology in ways that would not be possible if they were reliant on partnerships with commercial interests.

Mike Howell

Q&A

What are your feelings on receiving a Horizon Prize? 

Katrin Rittinger: Very happy and delighted that the work of our team has been recognised by this prize. Everyone involved has put an enormous amount of work and energy into this project and was open to adapt to new ways of working and willing to collaborate across disciplines and across institutions. This is a great recognition of everyone’s efforts and contributions.

What was your role within the team? 

Federica Raguseo: I am a postdoc working on phenotypic screening and target validation, as well as the communications lead for the partnership. My main role involves setting up biological assays and adapting them for fragment screening.

Caroline Hill: We developed the first-ever iPSC-based phenotypic differentiation screen of covalent fragments for the identification of potent inhibitors of signalling pathways and other molecular processes crucial for cell lineage specification. As the same signalling pathways that orchestrate early development are deregulated in diseases such as cancer, this work has provided an excellent proof of concept for the use of iPSC-based screens to identify therapeutically relevant compounds.

Why is this work so important and exciting? 

Andy Powell: Advances in genetics and genomic approaches are enabling the identification of novel protein targets for therapeutic modulation to mitigate disease; however, these targets are often considered intractable for small-molecule drugs. By combining chemical biology, chemoproteomics and phenotypic screening, our work has generated a large dataset linking small, drug-like molecules to proteins for which no previous small-molecule modulators have been identified, thereby presenting opportunities for broader drug discovery.

What were the biggest challenges in this project, and how did you overcome them? 

Paul Mercer: Overcoming the cultural and organisational barriers of working between industry and academia is often a challenge on a project of this size. GSK and the Crick have a unique relationship whereby GSK scientists are embedded in Crick groups working alongside each other to address scientific and sometimes logistical problems together, effectively nullifying barriers which might normally exist.

What different strengths did different people bring to the team?

Federica Raguseo: Given the vast multidisciplinary nature of the project, having a team with such diverse scientific expertise is a huge asset during project development. Regardless of the scientific question, the answer is always a quick chat away with the right team member.

Caroline Hill: The team brought together an impressive mix of biologists, chemists, data scientists and proteomics scientists from both academe and the pharmaceutical industry. The success of the partnership was the result of people with very different scientific perspectives working together on a common problem.

Where do you see the biggest impact of this technology being? 

Andy Powell: The technology developed through our collaborative project is already impacting drug discovery by enabling the identification of hit molecules against challenging protein targets. This impact within the pharmaceutical and biotechnology industry will broaden as the approach is adopted more widely. Furthermore, the approach is amenable for adoption by academic chemical biology research laboratories to enable the identification of small molecule tools to probe biological pathways across the bioscience field.

Mike Howell: This partnership will have a very significant legacy for discovery research at the Crick. The techniques developed and the knowledge gained are already bearing fruit and being used by researchers, either for novel probe and tool discovery or for phenotypic characterisation of novel chemicals being created for AMR projects. Its use as a research tool here and in other academic centres will only increase.

How will the technology be used in real life applications? 

Mike Howell: The beauty of the approaches, techniques and reagents used in this work is that they are likely to be readily available to many researchers in academia; in that sense, it is an enabler that can democratise probe and tool discovery, allowing many to explore specific areas of biology in ways that would not be possible if they were reliant on partnerships with commercial interests. And that is how new and unexpected discoveries are made.

Simon Boulton: The technology will be used to identify and develop new drug candidates against proteins that currently lack effective therapies. The broader platform and datasets could also become an industry-wide engine for faster, more precise drug discovery across many diseases.

How do you see this developing over the next few years? 

Simon Boulton: We expect the platform to scale dramatically, generating proteome-wide maps of ligandable sites and enabling the identification of covalent fragments for thousands of previously inaccessible proteins. The next phase will focus on translating these discoveries into therapeutics by advancing the most promising hit compounds through optimisation and drug discovery.

How important would you say collaboration is for producing high-quality science? How has collaboration influenced your work? 

Mike Howell: Collaborations like this are essentially a sandpit for two groups who usually work in slightly different ways to different agendas to come together and explore common ground, to work together and try things they maybe would have been able to try if following their usual ways of working. There simply wouldn’t have been the many different positive outcomes to this partnership if this hadn’t been a collaboration of equals; experts in their own fields who are prepared to try something different.

Paul Mercer: Translation of high-quality science needs a village. This project has brought together over 30 scientists and technology platform capabilities across the GSK and the Crick, informing technology development across both organisations which have highly impacted ways of working in both. This would not have been possible without a team willing to collaborate and work with each other on every level.