The increasingly atomic resolution of human biology presents an unprecedented opportunity for the innovation of definitive medicines for life-threatening diseases. Still, many well-defined, high-value protein targets remain beyond the limits of historical efforts in ligand discovery. Often challenging the discovery of therapeutics that disable intracellular proteins is the real or perceived limitation of small molecules to engage non-canonical protein folds and disrupt a biophysical or biochemical function. We have therefore undertaken to invest in the discipline of chemical biology as an organizing principle in drug discovery, so as to create vast numbers and new types of small molecules to advance the science of therapeutics. In this seminar, I will discuss progress in the field of targeted protein degradation, inspired by natural products and advances in chemical-induced dimerization. I will highlight both foundational research as well as our recent, first all-chemical approach that establishes design principles for new ligands, demonstrates extensibility to numerous cellular targets and informs mechanistic cellular biology. Importantly, lead optimization of chemical probes brings extraordinary (sub-nanomolar) potency, reveals catalyst-like activity, and now emanates first-in-class therapeutics. Finally, I will discuss learnings from our Targeted Protein Degradation Initiative, including curious challenges around which our ongoing research organizes.

Chemical induced dimerization for targeted protein degradation

2019 Fall National Meeting

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