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

Hetero-bifunctional PROteolysis TArgeting
Chimeras (PROTACs) represent
a new emerging class of small molecules designed to induce polyubiquitylation
and proteasomal-dependent degradation of a target protein. Despite
the increasing number of publications about the synthesis, biological
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’
chemical 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 P450 3A4 (CYP3A4) and human aldehyde
oxidase (hAOX) for more in-depth data interpretation,
and both enzymes resulted in active PROTAC metabolism.