7 strategies to improve PROTACs’ oral bioavailability 

[PROTAC image courtesy of Wikipedia]

PROteolysis TArgeting Chimera (PROTAC)* drugs emerged in 2001 as a novel therapeutic option for treating previously untreatable diseases. To date, no PROTAC drugs have earned U.S. FDA approval, but the technology has opened up a promising new chapter in drug discovery. PROTACs are being widely explored across both industry and academia and have expanded from treating cancer to immune disorders, neurodegenerative diseases, viral infections, etc.

A PROTAC molecule consists of three components: a ligand binding to a target protein, a ligand binding to E3 ligase and a linker. Unlike conventional small molecules that block target proteins via inhibition, PROTACs bind specifically to target proteins and induce their degradation by leveraging the ubiquitin-proteasome system (UPS). PROTACs’ binding process is referred to as a “chemical knockdown” approach.

PR…

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Tackling the DMPK challenges of developing PROTAC drugs 

PROTACs, or PROteolysis TArgeting Chimera, emerged as novel therapeutic modalities in 2001 but have only begun emerging from clinical trials (PROTAC® is a registered trademark of Arvinas. In this article, PROTAC specifically refers to the abbreviation of PROteolysis TArgeting Chimera as therapeutic modalities). PROTACs’ unique structures and modes of action (MOA) differentiate them from conventional small molecules and present exciting and unprecedented therapeutic opportunities. But questions remain about PROTACs’ broad-scale utility, given some of the pharmacological challenges scientists have uncovered during preclinical and clinical research.

In the first of a two-part series, we will showcase PROTACs’ unique structure and function, and highlight the challenges and strategies that PROTAC drug sponsors and developers should anticipate from the perspective of DMPK (drug metabolism and pharmacokinetics) studies. The second article in this series wil…

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