CAREER: Interrogating Kinetic Mechanisms of Targeted Protein Degradation at Scale

With the support of the CLP program in the Division of Chemistry, Professor Ferguson from the University of California, San Diego is developing experimental and theoretical frameworks for targeted protein degrader optimization. Targeted protein degradation is a strategy that employs bifunctional small molecules to recruit a target-of-interest to an E3-ligase, triggering target ubiquitination and proteasomal degradation. Despite being a valuable technique for creating tools and therapeutics, guiding principles for the optimization of degrader starting points into potent, selective and fast-acting compounds are lacking. This project seeks to develop the requisite chemistry, proteomic methodology and mathematical frameworks to evaluate current hypotheses at scale, and in doing so, uncover the rules of molecular recognition that govern efficient targeted protein degradation. In parallel, an integrative educational outreach component will be developed, giving high school students hands-on experience with TPD in the classroom. This research project seeks to evaluate the relative contributions of targeted protein degrader kinetic parameters across the kinome via the development of a ‘Kinetic Scout Degrader’ platform. To enable high-throughput and unbiased evaluation of these molecules, new chemoproteomic methods will be developed and used to measure in situ target engagement, ternary complex abundance and ternary complex co-operativity. Finally, these large datasets will be used to evaluate and train theoretical models of targeted protein degrader kinetics, that may be applied to any target-of-interest. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.