Special Chemical Biology Seminar
Zoom information available upon request.
The current lack of small molecule ligands, or "chemical probes", for disease-relevant proteins limits our understanding of disease biology and our ability to develop effective therapeutics. In this presentation, I will describe the use of chemical proteomics to expand the druggability of the proteome and guide the development of chemical probes with unique mechanisms of action, including for important therapeutic targets, such as the tyrosine kinase JAK1. JAK family kinases are responsible for signaling downstream of diverse cytokine receptors and are key targets for the treatment of autoimmune diseases and cancer. However, the clinical application of existing JAK inhibitors is restricted due to dose-limiting side-effects that arise from their poor selectivity between the 4 JAK isoforms: JAK1, JAK2, JAK3, and TYK2. Using chemical proteomics, we identified a druggable allosteric cysteine on JAK1 (C817) that is not conserved in JAK2 and JAK3. Optimization of a chemical probe targeting C817 yielded a potent JAK1 inhibitor (VVD-118313), which has unprecedented isoform selectivity and a unique mechanism of action to existing orthosteric drugs. The distinct pharmacological profile of VVD-118313 provides insight into cell-type specific differences in JAK-STAT signaling and the potential to differentially modulate the immune response. This research highlights the exciting potential of chemical proteomics to empower the discovery and development of allosteric chemical probes for other disease-relevant proteins.