Cited by 214Protein Degradation and InhibitorsChemical Synthesis and AnalysisProtein Structure and Dynamics

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Solution Conformations Shed Light on PROTAC Cell Permeability

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Atilaw, Yoseph, Poongavanam, Vasanthanathan, Svensson Nilsson, Caroline, Nguyen, Duy, Giese, Anja, Meibom, Daniel, Erdelyi, Mate, Kihlberg, Jan·2021·ACS Medicinal Chemistry Letters

DOI 10.1021/acsmedchemlett.0c00556PMC PMC7812666

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Abstract

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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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
ORCID: Atilaw, Yoseph
Poongavanam, Vasanthanathan
Meibom, Daniel
Erdelyi, Mate
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)
DOI: 10.1021/acsmedchemlett.0c00556
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
Licence: cc-by
pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html (vor)
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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Solution Conformations Shed Light on PROTAC Cell Permeability

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