Behind the Science: Lessons and Learnings with CSO, Matt Patricelli

Welcome to Behind the Science, where we dive into Vividion’s groundbreaking research, scientific approach, and clinical potential through conversations with the people driving these innovations.??

CSO Matt Patricelli was Vividion’s first employee and a founding scientist. He has seen the evolution of the company from early drug discovery to progressing these small molecules to clinical trials. This month, Matt will be sharing his “Lessons and learnings from eight years of chemoproteomics-centered drug discovery” with the British Pharmacological Society and Stanford Cancer Institute. Vividion’s CEO Aleksandra Rizo spoke with Matt to get a sneak preview of his presentation.

Read the Q&A below to learn about Matt’s insights.

Q&A with Matt Patricelli, CSO?

Aleksandra: This month, you will be sharing your lessons and learnings from your eight years at Vividion through two presentations. I understand that you will be talking about the scope of our screening campaigns and the progress that we have made across challenging targets, can you share some of your insights and why you think we have been so successful at drugging challenging targets?”

Matt: While reversible small molecule drug discovery has been most successful on target proteins that naturally bind to small molecule ligands or substrates, we have found through our chemoproteomics screening that the ability to achieve selective covalent reactions?using fragment elecrophiles is almost completely agnostic to target class. Our success rate in finding druggable pockets on transcription factors is roughly the same as our success rate on enzymes and receptors. So I think at the most fundamental level this is the underlying reason why our approach has been so prolific.

Aleksandra: I have heard you say that the allosteric pockets that we discover invariably exhibit “complex pharmacology,” which is quite surprising. Can you explain what you mean by this and how this ties into our approach?

Matt: This means that the functional impact of the small molecule binding to the target site depends to a large extent on the specific structure of the small molecule.?We have many examples now where we are able to either inhibit or activate a target by binding to the same site on the target protein with different small molecules. And, critical to considering the best discovery approach, we often find a significant subset of molecules that bind a potentially functional site actually have no functional impact at all. This means that traditional screening methods that focus on a functional outcome will miss binders that may enable the desired pharmacology through further chemistry optimization, which our approach is able to capture.

Vividion’s chemoproteomics-enabled, covalent-first discovery platform is perfectly suited to take advantage of these two fairly surprising observations. By focusing on the identification of selective covalent binding events with fragment-like starting points, regardless of functional outcome, we have been able to take advantage of a different set of rules for drug discovery that eliminates the bias for traditionally druggable target classes.

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