A Pharmacodynamic Model for the Assessment and Optimization of PROTACs

Small molecule proteolysis targeting chimeras (PROTACs) represent an exciting new therapeutic modality as they produce a knockdown phenotype while also carrying the potential for oral administration. Turning conventional inhibitors into PROTACs has proven to constitute a viable strategy for increasing potency and generating long-lasting pharmacological effects. However, many of the learnings from optimizing inhibitors are not directly applicable to PROTACs due to their fundamentally different mechanism of action.
Here, we examine this topic using a new comprehensive mathematical model that follows the four pillars of translational pharmacology up to biomarker readout. The model is applied to a variety of PROTAC compounds, both from literature as well as from in-house projects, yielding several key insights. First, we demonstrate how target exposure is translated to target engagement and then target degradation, pointing out the most critical parameters. Based on that mechanistic understanding, the basic Emax model is adapted to account for the peculiarities of the PROTAC concentration-response profile. Target degradation is further linked to biomarker readouts and the contribution of target inhibition to overall efficacy is evaluated. Finally, we discuss implications of our findings for drug discovery and we derive actionable strategies for the characterization and optimization of PROTACs.
The overarching aim of this talk is to allow researchers to tailor their experimental work and to arrive at a better understanding of their results, ultimately leading to more successful PROTAC discovery.