A Pharmacodynamic Model for the Assessment and Optimization of PROTACs
Robin T.U. Haid, MSc, PhD Student, Bayer AG, Preclinical Development, Drug
Metabolism and Pharmacokinetics, Preclinical Modeling and Simulation / ETH
Zurich, Institute of Pharmaceutical Sciences, Biopharmacy
Wednesday, September 13, 2023, 9:00 to 10:00 am PDT
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Abstract:
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.