Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 9, Pages 1732-1738Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00265
Keywords
Selective degradation; PAMPA; LPE; permeability; structure-permeability relationships
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Funding
- National Institute of General Medicine Studies of the National Institutes of Health [NIH R01GM131135]
- National Science Foundation GRFP [NSF DGE 1339067]
- UK Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J001201/2]
- European Research Council (ERC) [ERC-2012-StG311460 DrugE3CRLs]
- Italian Ministry of Education, University and Research (Miur)
- European Commission (Marie Sklodowska-Curie Actions Individual Fellowship) [H2020-MSCA-IF-2014-655516]
- BBSRC [BB/J001201/2] Funding Source: UKRI
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Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the proteasome. Most degraders lie outside the chemical space associated with most membrane-permeable drugs. Although many PROTACs have been described with potent activity in cells, our understanding of the relationship between structure and permeability in these compounds remains limited. Here, we describe a label-free method for assessing the permeability of several VH032-based PROTACs and their components by combining a parallel artificial membrane permeability assay (PAMPA) and a lipophilic permeability efficiency (LPE) metric. Our results show that the combination of these two cell-free membrane permeability assays provides new insight into PROTAC structure-permeability relationships and offers a conceptual framework for predicting the physicochemical properties of PROTACs in order to better inform the design of more permeable and more effective degraders.
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