Mathematical Model for Covalent Proteolysis Targeting Chimeras: Thermodynamics and Kinetics Underlying Catalytic Efficiency.

Proteolysis targeting chimeras (PROTACs), heterobifunctional protein degraders, have emerged as an exciting and transformative technology in chemical biology and drug discovery to degrade disease-causing proteins through co-opting of the ubiquitin-proteasome system (UPS). Here, we develop a mechanistic mathematical model for the use of irreversible covalent chemistry in targeted protein degradation (TPD) either to a target protein of interest (POI) or an E3 ligase ligand, considering the thermodynamic and kinetic factors governing ternary complex formation, ubiquitination, and degradation through the UPS. We highlight key advantages of covalency to the POI and E3 ligase and the underlying theoretical basis in the TPD reaction framework. We further identify regimes where covalency can serve to overcome weak binary binding affinities and improve the kinetics of ternary complex formation and degradation. Our results highlight the enhanced catalytic efficiency of covalent E3 PROTACs and thus their potential to improve the degradation of fast turnover targets.