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

Diego Garcia Jimenez; Maura Vallaro; Luigi Vitagliano; Lucia Lopez Lopez; Giulia Apprato; Giuseppe Ermondi; Giulia Caron

doi:10.5599/admet.2334

Authors

Diego Garcia Jimenez CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy https://orcid.org/0000-0002-7247-1480
Maura Vallaro CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy https://orcid.org/0000-0003-2735-6771
Luigi Vitagliano CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy https://orcid.org/0009-0003-6428-7901
Lucia Lopez Lopez CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy
Giulia Apprato CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy https://orcid.org/0000-0001-6906-2849
Giuseppe Ermondi CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy https://orcid.org/0000-0003-3710-3102
Giulia Caron CASSMedChem, Molecular Biotechnology and Health Sciences Dept., University of Torino, Piazza Nizza 44, 10126 Torino, Italy https://orcid.org/0000-0002-2417-5900

DOI:

https://doi.org/10.5599/admet.2334

Keywords:

bRo5, chameleonicity, ionization, lipophilicity, new chemical modalities, polarity, PROTAC

Abstract

Background and Purpose. The classical drug discovery toolbox continually expands beyond traditional rule of five (Ro5)-compliant small molecules to include new chemical modalities for difficult-to-drug targets. The paper focuses on the molecular properties essential to drive oral bioavailability within the bRo5 framework. Experimental Approach. The first part outlines the concept and methodologies for characterizing bRo5 physicochemical properties, including considerations on chameleonicity; in particular, the paper summarizes the content of the last author’s talk presented during the IAPC-10 Meeting held in Belgrade in September 2023 (https://iapchem.org/index.php/iapc-10-home). The second part of the manuscript presents novel experimental and computational data on three proteolysis targeting chimeras (PROTACs) currently in clinical trials. Key Results. Molecular descriptors of ARV-110, ARV-471, and DT-2216 are reported and the main limitations of the applied experimental approaches are discussed. Moreover, a simple computational method shows how predicting the presence of chameleonic effects. Conclusion. A full complete physicochemical characterization of three degraders in clinical trial is reported to highlight the differences in physicochemical descriptors between PROTACs dosed orally and intravenously.

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