Industry Perspective on the Pharmacokinetic and ADME Characterization of Heterobifunctional Protein Degraders

Laurie P Volak, Heide Marika Duevel, Sara Humphreys, David Nettleton, Colin Phipps, Andy Pike, Caroline Rynn, Paul Scott-Stevens, Donglu Zhang, Michael Zientek

Targeted protein degraders (TPDs), specifically the bifunctional protein degraders discussed in this manuscript, consist of two linked ligands for a protein of interest and an E3 ligase, resulting in molecules which largely violate accepted physicochemical limits (e.g. Lipinski's Rule of 5) for oral bioavailability. In 2021, the IQ Consortium Degrader DMPK/ADME Working Group undertook a survey of eighteen IQ member and non-member companies working on degraders to understand whether the characterization and optimization of these molecules were different from any other beyond the Rule of 5 (bRo5) compounds. Additionally, the working group sought to identify PK/ADME areas in need of further evaluation and where additional tools could aid in more rapid advancement of TPDs to patients. The survey revealed that although TPDs reside in a challenging bRo5 physicochemical space, most respondents focus their efforts on oral delivery. Physicochemical properties required for oral bioavailability were generally consistent across the companies surveyed. Many of the member companies used modified assays to address challenging degrader properties (e.g. solubility, non-specific binding), but only half indicated that they modified their drug discovery workflows. The survey also suggested the need for further scientific investigation in the areas of CNS penetration, active transport, renal elimination, lymphatic absorption, in silico/machine learning, and human pharmacokinetic prediction. Based on the survey results, the Degrader DMPK/ADME Working Group concludes that TPD evaluation does not fundamentally differ from other bRo5 compounds, but requires some modification compared to traditional small molecules and proposes a generic workflow for PK/ADME evaluation of bifunctional TPDs. Significance Statement Based on an industry survey, this article provides an understanding of the current state of ADME science pertaining to characterizing and optimizing targeted protein degraders, specifically bifunctional protein degraders, based upon the responses provided by 18 IQ consortium members and non-members developing targeted protein degraders to treat disease. Additionally, this article puts into context the differences / similarities in methods and strategies utilized for heterobifunctional protein degraders compared to other bRo5 molecules and those used for conventional small molecule drugs.