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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The linker can contribute to PROTAC solution conformation and degradation efficiency (DC50/Dmax), and influence E3 ligase-POI interactions and presentation of the POI within the zone of ubiquitylation.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citationEdmondson, S. D., Yang, B., & Fallan, C. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.030 · Cited by 422 · see citing works
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 387 · see citing works
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 286 · see citing works
Structure‐Based Design of a Macrocyclic PROTAC
Testa, A., Hughes, S. J., Lucas, X., Wright, J. E., & Ciulli, A. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201914396 · Cited by 251 · see citing works
Sebastiano, M. R., Doak, B. C., Backlund, M., Poongavanam, V., Over, B., Ermondi, G., Caron, G., Matsson, P., & Kihlberg, J. O. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00347 · Cited by 238 · see citing works
Self-citationChan, K.-H., Zengerle, M., Testa, A., & Ciulli, A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01912 · Cited by 222 · see citing works
Structural and conformational determinants of macrocycle cell permeability
Over, B., Matsson, P., Tyrchan, C., Artursson, P., Doak, B. C., Foley, M. A., Hilgendorf, C., Johnston, S. E., Lee, M. D., Lewis, R. J., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2203 · Cited by 209 · see citing works
Self-citationGramse, G., Dols-Pérez, A., Edwards, M. A., Fumagalli, L., & Gomila, G. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2013.02.011 · Cited by 199 · see citing works
Fundamental aspects of DMPK optimization of targeted protein degraders
Cantrill, C., Chaturvedi, P., Rynn, C., Schaffland, J. P., Walter, I., & Wittwer, M. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.03.012 · Cited by 169 · see citing works
Cicero, D. O., Barbato, G., & Bazzo, R. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00108a019 · Cited by 164 · see citing works
Developing degraders: principles and perspectives on design and chemical space
Maple, H. J., Clayden, N., Baron, A., Stacey, C., & Felix, R. L. (2019) · MedChemComm · doi:10.1039/c9md00272c · Cited by 159 · see citing works
Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
Klein, V. G., Townsend, C. E., Testa, A., Zengerle, M., Maniaci, C., Hughes, S. J., Chan, K.-H., Ciulli, A., & Lokey, R. S. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00265 · Cited by 153 · see citing works
Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs
Danelius, E., Poongavanam, V., Peintner, S., Wieske, L. H. E., Erdélyi, M., & Kihlberg, J. O. (2020) · Chemistry - A European Journal · doi:10.1002/chem.201905599 · Cited by 128 · see citing works
Self-citationUse of 3D Properties to Characterize Beyond Rule-of-5 Property Space for Passive Permeation
Guimarães, C. R. W., Mathiowetz, A. M., Shalaeva, M. Y., Goetz, G. H., & Liras, S. I. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci300010y · Cited by 117 · see citing works
Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space
Poongavanam, V., Doak, B. C., & Kihlberg, J. O. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.05.010 · Cited by 98 · see citing works
Self-citationHalogen Bonding: A Powerful Tool for Modulation of Peptide Conformation
Danelius, E., Andersson, H., Jarvoll, P., Lood, K., Gräfenstein, J., & Erdélyi, M. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00429 · Cited by 81 · see citing works
Mackman, R. L., Steadman, V. A., Dean, D. K., Jansa, P., Poullennec, K. G., Appleby, T. C., Austin, C., Blakemore, C. A., Cai, R. Z., Cannizzaro, C. E., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00802 · Cited by 79 · see citing works
Systematic Investigation of the Permeability of Androgen Receptor PROTACs
Scott, D. E., Rooney, T. P. C., Bayle, E. D., Mirza, T., Willems, H. M. G., Clarke, J. H., Andrews, S. P., & Skidmore, J. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00194 · Cited by 79 · see citing works
Narang, P., Bhushan, K., Bose, S., & Jayaram, B. (2005) · Physical Chemistry Chemical Physics · doi:10.1039/b502226f · Cited by 68 · see citing works
Nguyen, D., Lemos, C., Wortmann, L., Eis, K., Holton, S. J., Boemer, U., Moosmayer, D., Eberspaecher, U., Weiske, J., Lechner, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01606 · Cited by 44 · see citing works
Self-citationConformations of Laulimalide in DMSO-d6
Thepchatri, P., Cicero, D. O., Monteagudo, E. S., Ghosh, A. K., Cornett, B., Weeks, E. R., & Snyder, J. P. (2005) · Journal of the American Chemical Society · doi:10.1021/ja042890e · Cited by 43 · see citing works
Tyagi, M., Poongavanam, V., Lindhagen, M., Pettersen, A., Sjö, P., Schießer, S., & Kihlberg, J. O. (2018) · Organic Letters · doi:10.1021/acs.orglett.8b02447 · Cited by 40 · see citing works
Self-citationDegraders early developability assessment: face-to-face with molecular properties
Ermondi, G., Vallaro, M., & Caron, G. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.06.015 · Cited by 40 · see citing works
Danelius, E., Ohm, R. G., Ahsanullah, A., Mulumba, M., Ong, H., Chemtob, S., Erdélyi, M., & Lubell, W. D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00918 · Cited by 29 · see citing works
Dickman, R., Danelius, E., Mitchell, S. A., Hansen, D. F., Erdélyi, M., & Tabor, A. B. (2019) · Chemistry - A European Journal · doi:10.1002/chem.201902814 · Cited by 24 · see citing works
Conformational ensembles of flexible β-turn mimetics in DMSO-d6
Koivisto, J. J., Kumpulainen, E. T. T., & Koskinen, A. M. P. (2010) · Organic & Biomolecular Chemistry · doi:10.1039/b921794k · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
PROTACs: past, present and future
Li, K., & Crews, C. M. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00193d · Cited by 869 · see citing works
Targeted protein degradation: advances in drug discovery and clinical practice
Zhong, G., Chang, X., Xie, W., & Zhou, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02004-x · Cited by 326 · see citing works
A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Kofink, C. C., Trainor, N. B., Mair, B., Wöhrle, S., Wurm, M., Mischerikow, N., Roy, M. J., Bader, G., Greb, P., Garavel, G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33430-6 · Cited by 239 · see citing works
Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
Hu, Z., & Crews, C. M. (2022) · ChemBioChem · doi:10.1002/cbic.202100270 · Cited by 231 · see citing works
Cecchini, C., Pannilunghi, S., Tardy, S., & Scapozza, L. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.672267 · Cited by 198 · see citing works
PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery
Guedeney, N., Cornu, M., Schwalen, F., Kieffer, C., & Voisin‐Chiret, A. S. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.103395 · Cited by 178 · see citing works
Hendrick, C. E., Jorgensen, J. R., Chaudhry, C., Strambeanu, I. I., Brazeau, J.-F., Schiffer, J. M., Shi, Z., Venable, J. D., & Wolkenberg, S. E. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.2c00124 · Cited by 170 · see citing works
Dragovich, P. S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00141a · Cited by 161 · see citing works
Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity
Klein, V. G., Bond, A. G., Craigon, C., Lokey, R. S., & Ciulli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01496 · Cited by 152 · see citing works
Linker-Dependent Folding Rationalizes PROTAC Cell Permeability
Poongavanam, V., Atilaw, Y., Siegel, S., Giese, A., Lehmann, L. E., Meibom, D., Erdélyi, M., & Kihlberg, J. O. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00877 · Cited by 148 · see citing works
Self-citationGuerlavais, V., Sawyer, T. K., Carvajal, L. A., Chang, Y. S., Graves, B. J., Ren, J.-G., Sutton, D., Olson, K. A., Packman, K. E., Darłak, K., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00623 · Cited by 145 · see citing works
A bibliometric analysis of PROTAC from 2001 to 2021
Li, D., Yu, D., Li, Y., & Yang, R. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114838 · Cited by 122 · see citing works
Delivering on the promise of protein degraders
O’Brien, M. N., Luthra, S. A., Brown, M. F., & Bartlett, D. W. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00652-2 · Cited by 108 · see citing works
Designing Soluble PROTACs: Strategies and Preliminary Guidelines
Jiménez, D. G., Sebastiano, M. R., Vallaro, M., Mileo, V., Pizzirani, D., Moretti, E., Ermondi, G., & Caron, G. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00201 · Cited by 103 · see citing works
PROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works
Molecular chameleons in drug discovery
Poongavanam, V., Wieske, L. H. E., Peintner, S., Erdélyi, M., & Kihlberg, J. O. (2023) · Nature Reviews Chemistry · doi:10.1038/s41570-023-00563-1 · Cited by 96 · see citing works
Self-citationWeerakoon, D., Carbajo, R. J., Maria, L. D., Tyrchan, C., & Zhao, H. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c01036 · Cited by 94 · see citing works
Price, E., Weinheimer, M., Rivkin, A., Jenkins, G. J., Nijsen, M., Cox, P. B., & DeGoey, D. A. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02332 · Cited by 92 · see citing works
Molecular Strategies to Target Protein Aggregation in Huntington’s Disease
Jarosińska, O. D., & Rüdiger, S. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.769184 · Cited by 91 · see citing works
O’ Donovan, D. H., De Fusco, C., Kuhnke, L., & Reichel, A. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01577 · Cited by 83 · see citing works
Structural and Physicochemical Features of Oral PROTACs
Schade, M., Scott, J. S., Hayhow, T. G., Pike, A., Terstiege, I., Ahlqvist, M. M., Johansson, J. R., Diène, C. R., Fallan, C., Balazs, A., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01017 · Cited by 80 · see citing works
Advancing Strategies for Proteolysis-Targeting Chimera Design
Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01555 · Cited by 76 · see citing works
PROTAC Cell Permeability and Oral Bioavailability: A Journey Into Uncharted Territory
Poongavanam, V., & Kihlberg, J. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0208 · Cited by 72 · see citing works
Self-citationVHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives
Wang, C., Zhang, Y., Wang, J., & Xing, D. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113906 · Cited by 71 · see citing works
Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods
Mostofian, B., Martin, H., Razavi, A. M., Patel, S., Allen, B. K., Sherman, W., & Izaguirre, J. A. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00603 · Cited by 68 · see citing works
Teng, M., & Gray, N. S. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.020 · Cited by 63 · see citing works
Exploring the chemical space of orally bioavailable PROTACs
Apprato, G., Poongavanam, V., Jiménez, D. G., Atilaw, Y., Erdélyi, M., Ermondi, G., Caron, G., & Kihlberg, J. O. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.103917 · Cited by 67 · see citing works
Self-citationA beginner’s guide to current synthetic linker strategies towards VHL-recruiting PROTACs
Zografou-Barredo, N. A., Hallatt, A. J., Goujon-Ricci, J., & Cano, C. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117334 · Cited by 64 · see citing works
Volak, L. P., Duevel, H. M., Humphreys, S. C., Nettleton, D. O., Phipps, C. J., Pike, A., Rynn, C., Scott‐Stevens, P., Zhang, D., & Zientek, M. A. (2023) · Drug Metabolism and Disposition · doi:10.1124/dmd.122.001154 · Cited by 63 · see citing works
Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design
Mi, D., Li, Y., Gu, H., Li, Y., & Chen, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115444 · Cited by 57 · see citing works
Bashore, F. M., Foley, C. A., Ong, H. W., Rectenwald, J. M., Hanley, R. P., Norris-Drouin, J. L., Cholensky, S. H., Mills, C. A., Pearce, K. H., Herring, L. E., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.2c00804 · Cited by 56 · see citing works
Biotin’s Lessons in Drug Design
McConnell, D. B. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00975 · Cited by 55 · see citing works
Jiménez, D. G., Vallaro, M., Sebastiano, M. R., Apprato, G., D’Agostini, G., Rossetti, P., Ermondi, G., & Caron, G. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00823 · Cited by 55 · see citing works
Hirai, K., Yamashita, H., Tomoshige, S., Mishima, Y., Niwa, T., Ohgane, K., Ishii, M., Kanamitsu, K., Ikemi, Y., Nakagawa, S., et al. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00500 · Cited by 52 · see citing works
Moon, Y., Jeon, S. I., Shim, M. K., & Kim, K. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15020411 · Cited by 55 · see citing works
Plesniak, M. P., Taylor, E. K., Eisele, F., Kourra, C. M. B. K., Michaelides, I. N., Oram, A., Wernevik, J., Valencia, Z. S., Rowbottom, H., Mann, N., et al. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00314 · Cited by 51 · see citing works
Degraders upgraded: the rise of PROTACs in hematological malignancies
Casan, J. M. L., & Seymour, J. F. (2024) · Blood · doi:10.1182/blood.2023022993 · Cited by 52 · see citing works
Development of PROTAC Degrader Drugs for Cancer
Vetma, V., O’Connor, S., & Ciulli, A. (2024) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061824-105806 · Cited by 53 · see citing works
Impact of Linker Composition on VHL PROTAC Cell Permeability
Abeje, Y. E., Wieske, L. H. E., Poongavanam, V., Maassen, S., Atilaw, Y., Cromm, P. M., Lehmann, L. E., Erdélyi, M., Meibom, D., & Kihlberg, J. O. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02492 · Cited by 48 · see citing works
Self-citationThe cyclimids: Degron-inspired cereblon binders for targeted protein degradation
Ichikawa, S., Payne, N. C., Xu, W., Chang, C., Vallavoju, N., Frome, S., Flaxman, H. A., Mazitschek, R., & Woo, C. M. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.01.003 · Cited by 47 · see citing works
Sinatra, L., Vogelmann, A., Friedrich, F., Tararina, M. A., Neuwirt, E., Colcerasa, A., König, P., Toy, L., Yesiloglu, T. Z., Hilscher, S., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01385 · Cited by 45 · see citing works
Lessons learned in linking PROTACs from discovery to the clinic
Pike, A., Lee, E. C. Y., Michaelides, I. N., Schade, M., Sharma, A., Scott, J. S., & Srivastava, A. (2025) · Nature Reviews Chemistry · doi:10.1038/s41570-025-00784-6 · Cited by 48 · see citing works
Predictive Modeling of PROTAC Cell Permeability with Machine Learning
Poongavanam, V., Kölling, F., Giese, A., Göller, A. H., Lehmann, L. E., Meibom, D., & Kihlberg, J. O. (2023) · ACS Omega · doi:10.1021/acsomega.2c07717 · Cited by 45 · see citing works
Self-citationNew Approaches to Herbicide and Bioherbicide Discovery
Duke, S. O., Twitty, A., Baker, C. S., Sands, D. C., Boddy, L. G., Travaini, M. L., Sosa, G. M., Polidore, A. L. A., Jhala, A. J., Kloeber, J. M., et al. (2024) · Weed Science · doi:10.1017/wsc.2024.54 · Cited by 44 · see citing works
IFITM proteins assist cellular uptake of diverse linked chemotypes
Lou, K., Wassarman, D. R., Yang, T., Paung, Y., Zhang, Z., O’Loughlin, T. A., Moore, M. K., Egan, R. K., Greninger, P., Benes, C. H., et al. (2022) · Science · doi:10.1126/science.abl5829 · Cited by 42 · see citing works
Li, Z., Ren, G., Wang, X., Li, X., Ding, L., Zhu, J., Zhang, Y., Zhang, C., Zou, J., & Chen, X. S. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123387 · Cited by 42 · see citing works
Ermondi, G., Jiménez, D. G., Sebastiano, M. R., & Caron, G. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00298 · Cited by 40 · see citing works
Towards design of drugs and delivery systems with the Martini coarse-grained model
Kjølbye, L. R., Pereira, G. P., Bartocci, A., Pannuzzo, M., Albani, S., Marchetto, A., Jiménez‐García, B., Martin, J., Rossetti, G., Cecchini, M., et al. (2022) · QRB Discovery · doi:10.1017/qrd.2022.16 · Cited by 39 · see citing works
Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras
Zhao, C., & Dekker, F. J. (2022) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.2c00089 · Cited by 36 · see citing works
Chen, Z., Wang, M., Wu, D., Bai, L., Xu, T., Metwally, H., Wang, Y., McEachern, D., Zhao, L., Li, R., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02124 · Cited by 36 · see citing works
PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras
Madan, J., Ahuja, V. K., Dua, K., Samajdar, S., Ramchandra, M., & Giri, S. (2022) · BioDrugs · doi:10.1007/s40259-022-00551-9 · Cited by 36 · see citing works
PROTACs Targeting MLKL Protect Cells from Necroptosis
Rathje, O. H., Perryman, L., Payne, R. J., & Hamprecht, D. W. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00665 · Cited by 35 · see citing works
Macabuag, N., Esmieu, W., Breccia, P., Jarvis, R. E., Blackaby, W., Lazari, O., Urbonas, L., Eznarriaga, M., Williams, R., Strijbosch, A., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01149 · Cited by 34 · see citing works
Mslati, H., Gentile, F., Pandey, M. K., Ban, F., & Cherkasov, A. R. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c01878 · Cited by 34 · see citing works
IMHB-Mediated Chameleonicity in Drug Design: A Focus on Structurally Related PROTACs
Jiménez, D. G., Sebastiano, M. R., Vallaro, M., Ermondi, G., & Caron, G. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01200 · Cited by 34 · see citing works
Srivastava, A., Pike, A., Swedrowska, M., Nash, S. C., & Grime, K. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00358 · Cited by 34 · see citing works
Prediction of Chameleonic Efficiency
David, L., Wenlock, M. C., Barton, P., & Ritzén, A. (2021) · ChemMedChem · doi:10.1002/cmdc.202100306 · Cited by 34 · see citing works
Refinement of Computational Access to Molecular Physicochemical Properties: From Ro5 to bRo5
Sebastiano, M. R., Jiménez, D. G., Vallaro, M., Caron, G., & Ermondi, G. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00774 · Cited by 34 · see citing works
Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation
Faris, J. H., Adaligil, E., Popovych, N., Ono, S., Takahashi, M., Nguyen, H. Q., Plise, E. G., Taechalertpaisarn, J., Lee, H., Koehler, M. F. T., et al. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c10949 · Cited by 33 · see citing works
Property-based optimisation of PROTACs
Scott, J. S., Michaelides, I. N., & Schade, M. (2024) · RSC Medicinal Chemistry · doi:10.1039/d4md00769g · Cited by 32 · see citing works
Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds
Wieske, L. H. E., Atilaw, Y., Poongavanam, V., Erdélyi, M., & Kihlberg, J. O. (2022) · Chemistry - A European Journal · doi:10.1002/chem.202202798 · Cited by 30 · see citing works
Self-citationCecchini, C., Tardy, S., & Scapozza, L. (2022) · CHIMIA International Journal for Chemistry · doi:10.2533/chimia.2022.341 · Cited by 30 · see citing works
Conformational Sampling Deciphers the Chameleonic Properties of a VHL-Based Degrader
Ermondi, G., Jiménez, D. G., Sebastiano, M. R., Kihlberg, J. O., & Caron, G. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15010272 · Cited by 30 · see citing works
Self-citationProgress of small molecules for targeted protein degradation: PROTACs and other technologies
Zhao, H., Xin, M., & Zhang, S. (2023) · Drug Development Research · doi:10.1002/ddr.22026 · Cited by 31 · see citing works
Abbas, A., & Ye, F. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.134293 · Cited by 29 · see citing works
Salerno, A., Wieske, L. H. E., Diehl, C. J., & Ciulli, A. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c18354 · Cited by 29 · see citing works
T herapeutic targeting of chromatin: status and opportunities
Siklos, M. I., & Kubicek, S. (2021) · FEBS Journal · doi:10.1111/febs.15966 · Cited by 28 · see citing works
Challenges and Opportunities for In Vivo PROTAC Delivery
Benowitz, A. B., Scott‐Stevens, P., & Harling, J. D. (2021) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0223 · Cited by 29 · see citing works
Natural product-based PROteolysis TArgeting Chimeras (PROTACs)
Liu, M., Martyn, A. P., & Quinn, R. J. (2022) · Natural Product Reports · doi:10.1039/d2np00038e · Cited by 28 · see citing works
Tokarski, R. J., Sharpe, C., Huntsman, A. C., Mize, B. K., Ayinde, O. R., Stahl, E. H., Lerma, J. R., Reed, A., Carmichael, B., Muthusamy, N., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115342 · Cited by 28 · see citing works
Heitel, P. (2023) · Molecules · doi:10.3390/molecules28020690 · Cited by 27 · see citing works
Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs
Zhang, D., Ma, B., Dragovich, P. S., Ma, L., Chen, S., Chen, E. C., Ye, X., Liu, J., Pizzano, J., Bortolon, E., et al. (2024) · Communications Medicine · doi:10.1038/s43856-024-00505-y · Cited by 27 · see citing works
Feng, Y., Hu, X., & Wang, X. (2024) · Biomarker Research · doi:10.1186/s40364-024-00638-1 · Cited by 27 · see citing works
Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders
Bouvier, C., Lawrence, R., Cavallo, F., Xolalpa, W., Jordan, A. M., Hjerpe, R., & Rodríguez, M. S. (2024) · Cells · doi:10.3390/cells13070578 · Cited by 27 · see citing works
Analyzing the Linker Structure of PROTACs throughout the Induction Process: Computational Insights
Li, Y., Zhang, X., Xie, J., Meng, D., Liu, M., Chang, Y., Feng, G., Jiang, J., & Deng, P. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02637 · Cited by 24 · see citing works
Poongavanam, V., Peintner, S., Abeje, Y. E., Kölling, F., Meibom, D., Erdélyi, M., & Kihlberg, J. O. (2025) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5c00068 · Cited by 24 · see citing works
Self-citationAre we ready to design oral PROTACs®?
Jiménez, D. G., Sebastiano, M. R., Caron, G., & Ermondi, G. (2021) · ADMET & DMPK · doi:10.5599/admet.1037 · Cited by 24 · see citing works
Shaik, S., Gayam, P. K. R., Chaudhary, M., Singh, G., & Pai, A. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107868 · Cited by 23 · see citing works
Ensemble determination by NMR data deconvolution
Wieske, L. H. E., Peintner, S., & Erdélyi, M. (2023) · Nature Reviews Chemistry · doi:10.1038/s41570-023-00494-x · Cited by 23 · see citing works
Apprato, G., Caron, G., Deshmukh, G. S., Garcia-Jimenez, D., Haid, R. T. U., Pike, A., Reichel, A., Rynn, C., Zhang, D., & Wittwer, M. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2467195 · Cited by 23 · see citing works
Maurer, C. K., Fang, Z., Schindler, C., Pohl, G., Machrouhi, F., Lecomte, M., Petersson, C., & Duevel, H. M. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00854e · Cited by 22 · see citing works
Rational Proteolysis Targeting Chimera Design Driven by Molecular Modeling and Machine Learning
Tan, S., Chen, Z., Lu, R., Liu, H., & Yao, X. (2025) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.70013 · Cited by 23 · see citing works
Ishikawa, M., Tomoshige, S., & Sato, S. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00287 · Cited by 21 · see citing works
Evaluating physiochemical properties of FDA-approved orally administered drugs
Reese, T. C., Devineni, A., Smith, T., Lalami, I., Ahn, J., & Raj, G. V. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2275617 · Cited by 20 · see citing works
Jiménez, D. G., Ermondi, G., Jandová, Z., Vallaro, M., Caron, G., & Arnhof, H. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01497 · Cited by 18 · see citing works
Breaking free from the crystal lattice: Structural biology in solution to study protein degraders
Haubrich, K., Spiteri, V. A., Farnaby, W., Sobott, F., & Ciulli, A. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102534 · Cited by 18 · see citing works
CNS delivery of targeted protein degraders
Agarwal, P., Reid, D. L., & Amiji, M. M. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.06.057 · Cited by 17 · see citing works
Cellular parameters shaping pathways of targeted protein degradation
Cardno, A., Kennedy, B., & Lindon, C. (2025) · Communications Biology · doi:10.1038/s42003-025-08104-w · Cited by 17 · see citing works
Zamora, W. J., Viayna, A., Pinheiro, S., Curutchet, C., Bisbal, L., Ruiz, R., Ràfols, C., & Luque, F. J. (2023) · Physical Chemistry Chemical Physics · doi:10.1039/d3cp01428b · Cited by 17 · see citing works
Valencia, Z. S., Kingston, J. L. T., Miljković, F. N., Rowbottom, H., Mann, N., Davies, S., Ekblad, M., Castro, S. D., Kwapień, K., Malmerberg, E., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01642 · Cited by 15 · see citing works
Pang, X., Cui, D., Lv, B., & Wang, C. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02135 · Cited by 14 · see citing works
In vivo synthetic chemistry of proteolysis targeting chimeras (PROTACs)
Tomoshige, S., & Ishikawa, M. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116221 · Cited by 14 · see citing works
Pedrucci, F., Pappalardo, C., Marzaro, G., Ferri, N., Ferlin, A., & Toni, L. D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126630 · Cited by 14 · see citing works
Huber, M. E., Toy, L., Schmidt, M. F., Weikert, D., & Schiedel, M. (2022) · Chemistry - A European Journal · doi:10.1002/chem.202202565 · Cited by 14 · see citing works
Zhao, X., Chen, Y., Su, H., & Zhang, L. (2023) · Interdisciplinary medicine · doi:10.1002/inmd.20230004 · Cited by 14 · see citing works
Pushing the Limits of Characterising a Weak Halogen Bond in Solution
Peintner, S., & Erdélyi, M. (2021) · Chemistry - A European Journal · doi:10.1002/chem.202103559 · Cited by 13 · see citing works
Advancing target validation with PROTAC technology
Spitz, M. L., Kashkush, A., & Benhamou, R. I. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2490248 · Cited by 12 · see citing works
Next-generation isoform-selective fibroblast growth factor receptor inhibitors
Chen, L. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.09.004 · Cited by 12 · see citing works
A one-pot photocatalytic triazole-based linkerology for PROTACs
Liu, J., Deng, Y., Yin, J., Ji, J., Guan, C., Chen, X., Wu, X., Zhu, T., & Liu, S. (2024) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2024.102139 · Cited by 11 · see citing works
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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
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 ›
Are you an author, or do you see a problem with this page? Request a review
