Northwestern Chemistry welcomes Ken Hsu from the University of Texas at Austin, hosted by Xiaoyu Zhang.
Building Precision Chemistry to Probe Living Systems
A challenge in ligand and therapeutic discovery is the ability to target proteins that are considered intractable (often termed “undruggable”) due to the absence of well-defined binding pockets or the presence of shallow, featureless surfaces. Covalent chemistry has emerged as a powerful strategy to address this limitation by enabling the formation of selective bonds between small molecules and specific amino acid residues within orthosteric and allosteric protein sites. Approaches such as activity-based protein profiling (ABPP) combined with LC–MS/MS have driven significant advances in this area, particularly through the development of cysteine-reactive ligands that have expanded access to difficult-to-target proteins and biological pathways. However, cysteine residues are relatively rare in the human proteome, underscoring a key opportunity to broaden covalent targeting strategies to additional amino acids. In this seminar, I will discuss recent progress from my group in developing covalent chemistries that extend beyond cysteine to target residues such as lysine and tyrosine. I will highlight how these approaches are enabling new modes of protein inhibition and activation, provide examples of their application in cancer and immunology, and illustrate how expanding the scope of covalent targeting is opening new avenues for chemical biology and therapeutic discovery.
Anne Muller
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