Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity
Year: 2021
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
Institutions: University of California, Santa Cruz, University of Dundee
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: National Science Foundation, Wellcome Trust, Medical Research Scotland, European Commission, Innovative Medicines Initiative, National Institutes of Health, Horizon 2020 Framework Programme, Medical Research Council, National Institute of General Medical Sciences, Division of Graduate Education
Awards: G1233058420, G175265933, Cyclic peptide permeability, A Translational Engine for Biomedical Discoveries ., G2003881057, G383895836, G4255135185, G434337789, G4548891513, State-of-the-art facilities for structural biology at the University of Dundee., State-of-the-art facilities for structural biology at the University of Dundee., G5736694342, Gradute Research Fellowship Program (GRFP), G7011026087, EUbOPEN: Enabling and Unlocking biology in the OPEN, A Translational Engine for Biomedical Discoveries .
OpenAlex ID: W4225753704