Molecular properties, including chameleonicity, as essential tools for designing the next generation of oral beyond rule of five drugs

Background and Purpose: The classical drug discovery toolkit is expanding beyond traditional small molecules that comply with the Rule of Five (Ro5) to incorporate new chemical modalities for addressing challenging drug targets. This paper examines the molecular properties critical for achieving oral bioavailability within the beyond Ro5 (bRo5) framework.
Experimental Approach: The study begins by outlining the concepts and methodologies used to characterize the physicochemical properties of bRo5 compounds, with a particular focus on chameleonicity. Notably, it summarizes insights from the last author’s presentation at the IAPC-10 Meeting held in Belgrade in September 2023 (https://iapchem.org/index.php/iapc-10-home). The latter portion of the manuscript provides novel experimental and computational analyses of three proteolysis targeting chimeras (PROTACs) currently in clinical trials.
Key Results: The molecular descriptors of ARV-110, ARV-471, and DT-2216 are presented, alongside a discussion of the primary limitations of the experimental methodologies applied. Additionally, a straightforward computational method is introduced to predict chameleonic behavior in these compounds.
Conclusion: This study delivers a comprehensive physicochemical characterization of three clinical PROTAC degraders, highlighting key differences in descriptors between those designed for oral versus intravenous administration.