Understanding and Improving the Membrane Permeability of VH032-Based PROTACs

Victoria G. Klein, Chad E. Townsend, Andrea Testa, Michael Zengerle, Chiara Maniaci, Scott J. Hughes, Kwok-Ho Chan, Alessio Ciulli, R. Scott Lokey (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)1732-1738
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume11
Issue number9
Early online date30 Jul 2020
DOIs
Publication statusPublished - 10 Sep 2020

Keywords

  • Selective degradation
  • PAMPA
  • LPE
  • permeability
  • structure-permeability relationships

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