The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
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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Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00423-1 · Cited by 11,484
Molecular properties that influence the oral bioavailability of drug candidates
Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm020017n · Cited by 8,420
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960
Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.013 · Cited by 835
Self-citationEdmondson, S. D., Yang, B., & Fallan, C. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.030 · Cited by 422
Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection
DeGoey, D. A., Chen, H.-J., Cox, P. B., & Wendt, M. D. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00717 · Cited by 390
Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs
Whitty, A., Zhong, M., Viarengo‐Baker, L. A., Beglov, D., Hall, D. R., & Vajda, S. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.02.005 · Cited by 291
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Items 201–214 of 214
BindingDB Entry 50022907: Impact of Linker Composition on VHL PROTAC Cell Permeability.
BindingDB (2026) · UC San Diego · doi:10.7270/q29w0mcr
BindingDB Entry 50018797: A bibliometric analysis of PROTAC from 2001 to 2021.
BindingDB (2024) · UC San Diego · doi:10.7270/q28p64s7
BindingDB Entry 50021843: Structural and Physicochemical Features of Oral PROTACs.
BindingDB (2025) · UC San Diego · doi:10.7270/q2w09bm9
BindingDB Entry 50015833: Linker-Dependent Folding Rationalizes PROTAC Cell Permeability.
BindingDB (2023) · UC San Diego · doi:10.7270/q2qz2fzg
BindingDB (2024) · UC San Diego · doi:10.7270/q2vh5t9d
BindingDB (2024) · UC San Diego · doi:10.7270/q2pv6qt5
BindingDB Entry 50019409: PROTACs Targeting MLKL Protect Cells from Necroptosis.
BindingDB (2024) · UC San Diego · doi:10.7270/q2154ndd
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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