Lewis-Sigler Institute Faculty Candidate
Expanding the Druggable Proteome: Ligand and Target Discovery by Fragment-Based Screening in Cells
Advances in DNA sequencing and editing technologies have revolutionized our understanding of the genetic basis of human disease. However, many disease-relevant genes encode proteins that are poorly characterized and/or are considered “undruggable”, hindering our understanding of disease mechanisms and translating this knowledge into new therapies. Chemical probes offer a valuable way to directly interrogate the function and disease-relevance of proteins and can also serve as valuable leads for drug development, yet most proteins in the human proteome lack small-molecule ligands that can serve as probes. More generally, the boundaries, if any, on the ligandability, and therefore potential druggability, across the proteome remains poorly understood. In this seminar, I will describe a platform that integrates fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in cells. Many of these interactions can be site-specifically determined and involve proteins that fall outside of traditional druggable classes. We demonstrate that this knowledge can be advanced to furnish compounds that affect the activity of proteins heretofore lacking chemical probes. Furthermore, we integrated this platform with phenotypic screening to facilitate the identification of ligand-protein interactions that regulate complex cellular processes. Fragment-based screening in cells provides an extensive proteome-wide portrait of native protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.