Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity

Victoria G. Klein, Adam G. Bond, Conner Craigon, R. Scott Lokey (Lead / Corresponding author), Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)
244 Downloads (Pure)


Criteria for predicting the druglike properties of "beyond Rule of 5"Proteolysis Targeting Chimeras (PROTAC) degraders are underdeveloped. PROTAC components are often combined via amide couplings due to their reliability. Amides, however, can give rise to poor absorption, distribution, metabolism, and excretion (ADME) properties. We hypothesized that a bioisosteric amide-to-ester substitution could lead to improvements in both physicochemical properties and bioactivity. Using model compounds, bearing either amides or esters, we identify parameters for optimal lipophilicity and permeability. We applied these learnings to design a set of novel amide-to-ester-substituted, VHL-based BET degraders with the goal to increase permeability. Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect. These enhancements were driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution provides a simple strategy to enhance PROTAC permeability and bioactivity and may prove beneficial to other beyond Ro5 molecules.

Original languageEnglish
Pages (from-to)18082-18101
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number24
Early online date9 Dec 2021
Publication statusPublished - 23 Dec 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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