Chemical Proteomics: Realizing Therapeutic Potential – With Chris Parker

This year, Scripps Research is celebrating its 100-year anniversary! Their motto? Turning scientific inquiry into innovative treatments that benefit the world. In this series of articles, we aim to shine a spotlight on some of the leading analytical scientists at Scripps – and the crucial role their work plays in delivering on Scripps' raison d’etre. Here, Chris Parker, Associate Professor in the Department of Chemistry at Scripps, discusses his work in chemical proteomics – which is leading to the development of potential new therapies.

Proteomics has been around for a while, but I think it is experiencing a renaissance right now. For a long time, it more closely resembled the Wild West, with each lab having their own unique methods, reagents, software, etc. Now the field has matured and has become really user friendly and easy to practice – to the point where there are now commercial vendors offering standardized software, methods for quantitation, and numerous other tools and reagents for various applications. 

The field of proteomics has a strong history and presence here at Scripps – thanks to pioneers like John Yates and Ben Cravatt. Scripps has always appreciated the role of powerful technologies, such as MS-based proteomics, in driving scientific innovation and discovery. Investment in them have greatly benefited folks like me, who are not necessarily technologists themselves, but major users. 

My field, chemical proteomics, was really born out of activity-based protein profiling (ABPP) – a powerful strategy for global ligand and protein discovery utilizing proteomic technologies, innovated by Ben Cravatt and Matt Bogyo (Stanford) in the early 2000s. Since then, Ben has trained many academics that now have their own labs and are expanding the web of chemical proteomics in multiple different directions. ABPP has also led to several clinical candidates and is becoming an ever-increasing used discovery pipeline in biotech and pharma.

Most of ABPP strategies have focused on the use of covalent probes, which require a reactive group on the protein to aide in their detection by MS and is often performed in lysates. Our strategy does not require such reactive groups and instead employs photoaffinity probes – probes that can capture transient protein–small molecule interactions upon exposure to UV light. Photoaffinity approaches have long been used to identify the targets of bioactive compounds and to monitor various other interactions. However, we were the first to realize the potential of integrating photoaffinity probes with the broad discovery concepts of ABPP. Specifically, we’ve generated specialized libraries of photoaffinity probes that allow us to globally profile the ability of proteins to non-covalently bind to drug like small molecules, directly in living cells. Upon binding to proteins, we photoactivate the probes to capture these interactions, and then enrich them from the rest of the proteome and then identify and quantify via MS. From this information, we can gather information about the binding sites, binding pocket occupancy and relative affinities, in theory, on any protein and pocket, directly in live cells. This information can be used to understand the activity of compounds or to develop new compounds with novel activity to help elucidate biological functions and explore therapeutic opportunities.

Technology in action
 

We are now confident in our methods, so are focused on applying them to solve problems of human health. We recently published a study where we use our technology to develop a first-in-class inhibitor for a protein that plays a key role in autoimmune and autoinflammatory conditions – and I think it offers a great example of why our work is so important. 

The starting point for this work was the discovery of correlations between people that have autoimmune disease and mutations in this gene, which makes it a great drug target. But the problem was, nobody knew what it did because it is such a complex protein and there is no direct functional readout. With our technology, we successfully developed inhibitors and other chemical tools and used them to dissect the protein’s functions and disease roles. I think this is amazing, because we went from not knowing the function to realizing its therapeutic potential.

We are now replicating what we were able to do with this platform to find unique druggable targets in other disease states, including cancer. And it’s an understatement to say we are excited about the potential of our technology in these applications.

_{Headshot - Credit: Supplied by Author | Hero Credit - Images supplied by Scripps Research}