In vitro and in vivo ADME of heterobifunctional degraders: a tailored approach to optimize DMPK properties of PROTACs©.

ABSTRACT: Proteolysis-targeting chimeras (PROTACs©) have recently emerged as a promising new drug modality. Residing beyond the rule-of-five space, they pose challenges in terms of physicochemical properties. With this study, we contribute to enhancing the understanding of their early ADME characterization. For permeability assessment, transwell assays such as Caco-2 remain challenging. Although the addition of serum may reduce unspecific binding and improve recovery, the assay was not found predictive for absorption. As a surrogate, we propose to focus optimization on molecular descriptors and support a preferred space for oral PROTACs© with ≤3 H-bond donors (HBDs), molecular weight (MW) ≤950 Da and number of rotatable bonds ≤12. We have developed a predictive score serving as initial guidance for

SUBMITTER: Maurer CK 

PROVIDER: S-EPMC11843253 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature