Molecular Properties Of PROTACs And The Relationship To Formulation Design

By Dr. Michael Grass, Ph.D. – Head of Innovation and Dr. David Vodak, Ph. D. – Chief Scientific Officer, Bend Bioscience

Targeted protein degraders (TPDs) represent a revolutionary class of therapeutics with the potential to address a wide range of unmet medical needs. Despite their promise, the successful development of TPD-based drugs faces significant formulation and delivery challenges due to their complex molecular properties. These challenges are particularly evident in both injectable and oral formulations, with oral delivery being the most problematic. TPDs, especially PROTACs (Proteolysis Targeting Chimeras), often suffer from extremely low bioavailability, primarily due to poor solubility, limited permeability, and instability within the gastrointestinal tract.

In this paper, we conduct a comprehensive analysis of diverse PROTAC structures, evaluating their calculated physicochemical properties to identify key trends contributing to their low oral bioavailability. We then explore formulation strategies to overcome these barriers, with a focus on amorphous solid dispersions (ASDs) and, more specifically, spray-dried dispersion (SDD) technology. By leveraging these advanced formulation approaches, we demonstrate how dissolution rate, solubility, and absorption can be enhanced, ultimately improving the feasibility of oral PROTAC therapeutics.