Arvinas has pioneered the development of PROteolysis TArgeting Chimeras, or PROTAC® protein degraders, which are heterobifunctional, modular small molecules engineered to induce the degradation of disease-causing proteins using the ubiquitin-proteasome system. A PROTAC molecule consists of a ligand region (“warhead”) that binds to the target protein of interest, an E3 ubiquitin ligase recruiting ligand, and a connecting linker region which orients the target protein and E3 ligase for optimal ternary complex formation and subsequent ubiquitylation. The unique design of each of these regions, in concert with one another, plays a role in the specificity and potency of PROTAC mediated target degradation. The use of biophysical assays such as surface plasmon resonance (SPR), microscale thermophoresis (MST), thermal shift assays (TSA), and affinity selection mass spectroscopy (ASMS) to characterize and optimize the binding activity of each region of these small molecules, both in isolation and as part of a ternary complex, provides critical data toward the development of a highly functional PROTAC. These biophysical assays are part of an extensive suite of tools fueling our PROTAC® Discovery Engine. In this presentation we will discuss how deeply understanding target and E3 ligase ligand attributes allows for the optimization and prioritization of PROTAC molecules that are best suited for drug discovery.

PROTAC® biophysical characterization fuels the discovery of target and E3 ligase ligands for the discovery of optimized PROTAC protein degrader molecules

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