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Metabolism of PROTACs

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 a collection of PROTACs in cryopreserved human hepatocytes, and vs CYP3A4 and aldehyde oxidase. 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.

Interestingly the authors observed potential metabolism by aldehyde oxidase on a substituted thiazole, and 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

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