Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective.

Drug Discovery Today
Andy PikeDermot F McGinnity

Abstract

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality with the potential to open target space not accessible to conventional small molecules via a degradation-based mechanism; however, their bifunctional nature can result in physicochemical properties that breach commonly accepted limits for small-molecule oral drugs. We offer a drug metabolism and pharmacokinetics (DMPK) perspective on the optimisation of oral PROTACs across a diverse set of projects within Oncology R&D at AstraZeneca, highlighting some of the challenges that they have presented to our established screening cascade. Furthermore, we challenge some of the perceptions and dogma surrounding the feasibility of oral PROTACS and demonstrate that acceptable oral PK properties for this modality can be regularly achievable despite the physicochemical property challenges they present.

Citations

Feb 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Giuseppe ErmondiGiulia Caron
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bernat Coll-MartínezBernat Crosas
Mar 4, 2021·Cell Chemical Biology·Chiho KimYonghao Yu
May 14, 2021·Journal of Medicinal Chemistry·Paul D LeesonAndrew R Leach
Jun 1, 2021·Current Opinion in Pharmacology·Joel O Cresser-BrownHannah J Maple
May 25, 2021·Frontiers in Molecular Biosciences·Matylda Anna IzertMaria Wiktoria Górna
Jun 17, 2021·Nature Reviews. Cancer·Brandon DaleJian Jin
Apr 30, 2021·Drug Metabolism Reviews·S Cyrus KhojastehCong Wei
Jun 29, 2021·Journal of Medicinal Chemistry·Shaowen XieShengtao Xu
Jul 22, 2021·Nature Reviews. Drug Discovery·Melanie SchneiderAndrew R Leach
Oct 16, 2020·Journal of Medicinal Chemistry·Liqun ChenJing Liu
Aug 23, 2021·Drug Discovery Today·Scott J HughesIan Churcher
Aug 26, 2021·Journal of Medicinal Chemistry·Afjal H MiahJohn D Harling
Sep 9, 2021·Chembiochem : a European Journal of Chemical Biology·Zhenyi Hu, Craig M Crews
Sep 30, 2021·Future Medicinal Chemistry·Vasanthanathan Poongavanam, Jan Kihlberg
Nov 15, 2021·Drug Discovery Today·Kit-Kay MakMallikarjuna Rao Pichika

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