Metabolism of PROTACs
An understanding of the metabolism of PROTACs is a growing need since their metabolism can’t be readily predicted from the individual ligands that constitute the chimera.
A paper by Goracci et al. looks at the metabolic stability of 40 PROTACs in cryopreserved human hepatocytes, and the involvement of CYP3A4 and aldehyde oxidase. Although the metabolism of these molecules could not be predicted from that of their constituent ligands, the linker appears to be the most labile moiety, with any instability localized at the attachment points. Depending on the type of linker, O- and N-dealkylations were observed.
Due to the size of its active site, CYP3A4 is proposed to play an essential role in metabolism of PROTACs. However, the authors also observed metabolism by aldehyde oxidase, specifically involving hydroxylation of the a 4-methyl-5-phenyl-thiazole moiety of VHL ligands. The authors are currently widening their studies to further investigate metabolism of PROTACs by this enzyme.
Reference
Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications. Goracci, et al. Journal of Medicinal Chemistry 2020 63 (20), 11615-11638
