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Solution Conformations Shed Light on PROTAC Cell Permeability
Open accessAbstract
Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.
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“The linker can contribute to the PROTAC solution conformation68 and degradation efficiency (DC50/Dmax)69, and influence the E3 ligase–POI interactions and presentation of the POI within the zone of ubiquitylation (Fig. 5).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [68]
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Metadata
- Authors
- Atilaw, Y., Poongavanam, V., Svensson Nilsson, C., Nguyen, D., Giese, A., Meibom, D., Erdelyi, M., & Kihlberg, J.
- Affiliations
- Uppsala University (SE)
- Uppsala University , , ,
- Nuvisan (Germany) (DE)
- Bayer (Germany) (DE)
- Corresponding author
- Kihlberg, Jan
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-12-25
- Volume
- 12
- Issue
- 1
- Pages
- 107-114
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC7812666
- OpenAlex
- W3117557114
- Cited by
- 208
- References
- 33
- Citations by year
- 2026: 39 · 2025: 33 · 2024: 40 · 2023: 35 · 2022: 37 · 2021: 24
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- Funders
- Bayer (NA)
- Vetenskapsrådet (2016-03602, 2016-05160)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- PROTACs, membrane permeability, solution conformation, polar surface area, hydrogen bonding, π-π stacking, intracellular protein degradation, ADME properties
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