Products Cited in Publications Worldwide Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications

Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications

Goracci, Laura; Desantis, Jenny; Valeri, Aurora; Castellani, Beatrice; Eleuteri, Michela; Cruciani, Gabriele

DOI: PMID:

Abstract

Hetero-bifunctional PROteolysis TArgeting Chimeras (PROTACs) represent a new emerging class of small mols. designed to induce polyubiquitylation and proteasomal-dependent degradation of a target protein. Despite the increasing number of publications about the synthesis, biol. evaluation, and mechanism of action of PROTACs, the characterization of the pharmacokinetic properties of this class of compounds is still minimal. Here, we report a study on the metabolism of a series of 40 PROTACs in cryopreserved human hepatocytes at multiple time points. Our results indicated that the metabolism of PROTACs could not be predicted from that of their constituent ligands. Their linkers' chem. nature and length resulted in playing a major role in the PROTACs' liability. A subset of compounds was also tested for metabolism by human cytochrome P 450 3A4 (CYP3A4) and human aldehyde oxidase (hAOX) for more in-depth data interpretation, and both enzymes resulted in active PROTAC metabolism

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