Advances in DNA sequencing and editing technologies have revolutionized our understanding of the molecular basis of many human diseases. 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 native proteomes remains poorly understood. In this seminar, I will describe our lab’s efforts to develop powerful chemical proteomic strategies to broadly map ligandable proteins directly in cells, and how this information can be advanced into useful chemical probes. In particular, I will highlight how these methods can be used to generate chemical probes for members of the solute carrier (SLC) protein family. SLCs are the largest family of transporters and play pivotal roles in a wide variety of physiological and pathophysiological processes; yet they are pharmacologically underexploited relative to other protein families of similar stature. This dearth is due to, in part, unique technical hurdles they pose for traditional screening methods, underlying the need for new approaches for SLC chemical probe discovery. I will focus on our development of first-in-class chemical probes for SLC15A4, an endolysosomal protein with strong ties to inflammation and autoimmunity, and their utility in understanding SLC15A4-mediated biology.

Chemoproteomic approaches for SLC chemical probe discovery

ACS Spring 2022

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