Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity
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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.
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ARV-771 and MZ1 displayed distinct intra-BET bromodomain cooperativity profiles in FP ternary complex assays.
“ARV-771 and MZ1 displayed distinct intra-BET bromodomain cooperativity profiles in FP ternary complex assays46.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [46]
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Self-citationPROTAC degraders as chemical probes for studying target biology and target validation
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- Authors
- Klein, V. G., Bond, A. G., Craigon, C., Lokey, R. S., & Ciulli, A.
- Affiliations
- University of California, Santa Cruz (US)
- University of Dundee (GB)
- Corresponding author
- Lokey, R. Scott
- Ciulli, Alessio
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-12-09
- Volume
- 64
- Issue
- 24
- Pages
- 18082-18101
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC8713283
- OpenAlex
- W4225753704
- Cited by
- 152
- References
- 79
- Citations by year
- 2026: 36 · 2025: 30 · 2024: 29 · 2023: 27 · 2022: 29 · 2021: 1
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion, cc-by)
- ChemRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Funders
- Medical Research Scotland (1170-2017)
- Division of Graduate Education (DGE 1339067)
- Wellcome Trust (094090/Z/10/Z, 100476/Z/12/Z)
- Horizon 2020 Framework Programme (875510)
- National Institute of General Medical Sciences (R01GM131135)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- PROTAC degraders, bioisosterism, membrane permeability, lipophilicity, ADME properties, hook effect, ternary complex formation, intracellular stability
- MeSH terms
- Amides, Animals, Cell Membrane Permeability, Dogs, Esters, Hydrogen Bonding, Ligands, Oligopeptides, Reproducibility of Results, Ubiquitin-Protein Ligases, Proteolysis, Madin Darby Canine Kidney Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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