Plasticity of the Cullin-RING Ligase Repertoire Shapes Sensitivity to Ligand-Induced Protein Degradation
Open accessAbstract
Inducing protein degradation via small molecules is a transformative therapeutic paradigm. Although structural requirements of target degradation are emerging, mechanisms determining the cellular response to small-molecule degraders remain poorly understood. To systematically delineate effectors required for targeted protein degradation, we applied genome-scale CRISPR/Cas9 screens for five drugs that hijack different substrate receptors (SRs) of cullin RING ligases (CRLs) to induce target proteolysis. We found that sensitivity to small-molecule degraders is dictated by shared and drug-specific modulator networks, including the COP9 signalosome and the SR exchange factor CAND1. Genetic or pharmacologic perturbation of these effectors impairs CRL plasticity and arrests a wide array of ligases in a constitutively active state. Resulting defects in CRL decommissioning prompt widespread CRL auto-degradation that confers resistance to multiple degraders. Collectively, our study informs on regulation and architecture of CRLs amenable for targeted protein degradation and outlines biomarkers and putative resistance mechanisms for upcoming clinical investigation.
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Target identification and elucidation of the mechanism of action of degraders via functional genomics was initially mostly driven by pooled CRISPR/Cas9 screens with a positive selection readout based on cellular fitness.
“Target identification and elucidation of the mechanism of action of degraders via functional genomics was initially mostly driven by pooled CRISPR/Cas9 screens with a positive selection readout based on cellular fitness (“drug resistance screens”).168,232,233”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [233]
CRBN loss is inconsequential for KBM7 proliferation.
“Previous studies have shown that CRBN loss is inconsequential for KBM7 proliferation15.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [15]
Most emerging mutations occur directly in the SR of the involved E3 ligase.
“In line with previous studies that employed CRISPR/Cas9 screens13–15, we show that most emerging mutations occur directly in the SR of the involved E3 ligase.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [15]
Impaired UBE2M function confers degrader resistance through inactivation of a substantial number of CRL complexes.
“UBE2M is an essential E2 enzyme in the neddylation cascade whose impaired function confers degrader resistance through the inactivation of a substantial number of CRL complexes.141”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [141]
Several functional genomics campaigns have helped map how the repertoire of CRLs and their regulators shape degrader efficacy, outlining putative resistance mechanisms.
“Several functional genomics campaigns in recent years have helped map how the repertoire of CLRs and their regulators shape degrader efficacy, thus also outlining putative resistance mechanisms.141-151”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [141]
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Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 671 · see citing works
Protein degraders enter the clinic — a new approach to cancer therapy
Chirnomas, D., Hornberger, K. R., & Crews, C. M. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00736-3 · Cited by 658 · see citing works
Targeted protein degradation: from mechanisms to clinic
Tsai, J. M., Nowak, R. P., Ebert, B. L., & Fischer, E. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00729-9 · Cited by 438 · see citing works
Rational discovery of molecular glue degraders via scalable chemical profiling
Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., Kaltheuner, I. H., Hahn, E., Seiler, K., Koren, A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0594-x · Cited by 369 · see citing works
Self-citationTargeted 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
Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
Alabi, S. B., & Crews, C. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100647 · Cited by 271 · see citing works
Diehl, C. J., & Ciulli, A. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00387b · Cited by 259 · see citing works
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
Imaide, S., Riching, K. M., Makukhin, N., Vetma, V., Whitworth, C., Hughes, S. J., Trainor, N., Mahan, S. D., Murphy, N., Cowan, A. D., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00878-4 · Cited by 251 · see citing works
Surka, C., Jin, L., Mbong, N., Lu, C.-C., Jang, I. S., Rychak, E., Mendy, D., Clayton, T., Tindall, E., Hsu, C., et al. (2021) · Blood · doi:10.1182/blood.2020008676 · Cited by 229 · see citing works
Targeted protein degradation for cancer therapy
Hinterndorfer, M., Spiteri, V. A., Ciulli, A., & Winter, G. E. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00817-8 · Cited by 245 · see citing works
Self-citationTargeted protein degradation via intramolecular bivalent glues
Hsia, O., Hinterndorfer, M., Cowan, A. D., Iso, K., Ishida, T., Sundaramoorthy, R., Nakasone, M. A., Imrichova, H., Schätz, C., Rukavina, A., et al. (2024) · Nature · doi:10.1038/s41586-024-07089-6 · Cited by 222 · see citing works
Self-citationPrey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective
Luh, L. M., Scheib, U., Juenemann, K., Wortmann, L., Brands, M., & Cromm, P. M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004310 · Cited by 200 · see citing works
Chasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
Self-citationAhn, G., Riley, N. M., Kamber, R. A., Wisnovsky, S., von Hase, S. M., Bassik, M. C., Banik, S. M., & Bertozzi, C. R. (2023) · Science · doi:10.1126/science.adf6249 · Cited by 197 · see citing works
Drummond, M. L., Henry, A., Li, H., & Williams, C. I. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00897 · Cited by 166 · see citing works
Molecular Glue Discovery: Current and Future Approaches
Dewey, J. A., Delalande, C., Azizi, S., Lu, V., Antonopoulos, D. A., & Babnigg, G. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00449 · Cited by 147 · see citing works
Steinebach, C., Ng, Y. L. D., Sosič, I., Lee, C.-S., Chen, S., Lindner, S., Vu, L. P., Bricelj, A., Haschemi, R., Monschke, M., et al. (2020) · Chemical Science · doi:10.1039/d0sc00167h · Cited by 148 · see citing works
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Hanzl, A., Casement, R., Imrichova, H., Hughes, S. J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01177-2 · Cited by 133 · see citing works
Self-citationOvercoming Cancer Drug Resistance Utilizing PROTAC Technology
Burke, M. R., Smith, A. R., & Zheng, G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.872729 · Cited by 126 · see citing works
Shirasaki, R., Matthews, G. M., Gandolfi, S., de Matos Simoes, R., Buckley, D. L., Raja Vora, J., Sievers, Q. L., Brüggenthies, J. B., Dashevsky, O., Poarch, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108532 · Cited by 123 · see citing works
COP9 signalosome: Discovery, conservation, activity, and function
Qin, N., Xu, D., Li, J., & Deng, X. W. (2020) · Journal of Integrative Plant Biology · doi:10.1111/jipb.12903 · Cited by 119 · see citing works
TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains
Kaiho-Soma, A., Akizuki, Y., Igarashi, K., Endo, A., Shoda, T., Kawase, Y., Demizu, Y., Naito, M., Saeki, Y., Tanaka, K., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.023 · Cited by 110 · see citing works
Bensimon, A., Pizzagalli, M. D., Kartnig, F., Dvorak, V., Essletzbichler, P., Winter, G. E., & Superti-Furga, G. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.04.003 · Cited by 102 · see citing works
Self-citationProteolysis targeting chimeras (PROTACs) in cancer therapy
Ocaña, A., & Pandiella, A. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01672-1 · Cited by 87 · see citing works
Piperlongumine conjugates induce targeted protein degradation
Pei, J., Xiao, Y., Liu, X., Hu, W., Sobh, A., Yuan, Y., Zhou, S., Hua, N., Mackintosh, S. G., Zhang, X., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.01.004 · Cited by 84 · see citing works
The rise and rise of protein degradation: Opportunities and challenges ahead
Hughes, S. J., Testa, A., Thompson, N., & Churcher, I. (2021) · Drug Discovery Today · doi:10.1016/j.drudis.2021.08.006 · Cited by 83 · see citing works
PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network
Reichermeier, K. M., Straube, R., Reitsma, J. M., Sweredoski, M. J., Rose, C. M., Moradian, A., den Besten, W., Hinkle, T., Verschueren, E., Petzold, G., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.013 · Cited by 78 · 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
Sellar, R. S., Sperling, A. S., Slabicki, M. M., Gasser, J. A., McConkey, M. E., Donovan, K. A., Mageed, N., Adams, D. N., Zou, C., Miller, P. G., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci153514 · Cited by 75 · see citing works
Transforming targeted cancer therapy with PROTACs: A forward-looking perspective
Farnaby, W., Koegl, M., McConnell, D. B., & Ciulli, A. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.02.009 · Cited by 65 · see citing works
The COP9 signalosome: A versatile regulatory hub of Cullin-RING ligases
Schulze, E., & Naumann, M. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2022.08.003 · Cited by 66 · see citing works
Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders
Gosavi, P. M., Ngan, K. C., Yeo, M. J. R., Su, C., Li, J., Lue, N. Z., Hoenig, S. M., & Liau, B. B. (2022) · ACS Central Science · doi:10.1021/acscentsci.1c01603 · Cited by 56 · see citing works
Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions
Cossar, P. J., Wolter, M., Dijck, L. V., Valenti, D., Levy, L. M., Ottmann, C., & Brunsveld, L. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c03035 · Cited by 56 · see citing works
Molecular glues and induced proximity: An evolution of tools and discovery
Robinson, S. A., Co, J., & Banik, S. M. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.04.001 · Cited by 54 · see citing works
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50 · see citing works
Self-citationSelective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer
Pu, C., Tong, Y., Liu, Y., Lan, S., Wang, S., Yan, G., Zhang, H., Luo, D., Ma, X., Yu, S., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114321 · Cited by 50 · see citing works
Systemwide disassembly and assembly of SCF ubiquitin ligase complexes
Baek, K., Scott, D. C., Henneberg, L. T., King, M. T., Mann, M., & Schulman, B. A. (2023) · Cell · doi:10.1016/j.cell.2023.02.035 · Cited by 47 · see citing works
Selectivity through Targeted Protein Degradation (TPD)
Gopalsamy, A. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00397 · Cited by 46 · see citing works
Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting
Li, J., Purser, N., Liwocha, J., Scott, D. C., Byers, H. A., Steigenberger, B. A., Hill, S., Tripathi‐Giesgen, I., Hinkle, T. B., Hansen, F. M., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.01.022 · Cited by 45 · see citing works
The emerging roles of non-canonical ubiquitination in proteostasis and beyond
Akizuki, Y., Kaypee, S., Ohtake, F., & Ikeda, F. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202311171 · Cited by 45 · see citing works
cIAP1-based degraders induce degradation via branched ubiquitin architectures
Akizuki, Y., Morita, M., Mori, Y., Kaiho-Soma, A., Dixit, S., Endo, A., Shimogawa, M., Hayashi, G., Naito, M., Okamoto, A., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01178-1 · Cited by 44 · see citing works
Mechanism of millisecond Lys48-linked poly-ubiquitin chain formation by cullin-RING ligases
Liwocha, J., Li, J., Purser, N., Rattanasopa, C., Maiwald, S. A., Krist, D. T., Scott, D. C., Steigenberger, B. A., Prabu, J. R., Schulman, B. A., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01206-1 · Cited by 44 · see citing works
Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation
Kagiou, C., Cisneros, J. A., Farnung, J., Liwocha, J., Offensperger, F., Dong, K. D., Yang, K., Tin, G., Horstmann, C. S., Hinterndorfer, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49739-3 · Cited by 43 · see citing works
Self-citationInduced proximity-based therapeutic modalities
King, E. A., Meyers, M., & Nomura, D. K. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01316-z · Cited by 42 · see citing works
E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance
Hanzl, A., Barone, E., Bauer, S., Yue, H., Nowak, R. P., Hahn, E., Pankevich, E. V., Koren, A., Kubicek, S., Fischer, E. S., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c10784 · Cited by 41 · see citing works
Self-citationIdentification and selectivity profiling of small-molecule degraders via multi-omics approaches
Scholes, N. S., Mayor‐Ruiz, C., & Winter, G. E. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.007 · Cited by 41 · see citing works
Self-citationHigh-throughput ligand diversification to discover chemical inducers of proximity
Shaum, J. B., Ordoño, M. M. I., Steen, E. A., Wenge, D. V., Cheong, H., Janowski, J., Hunkeler, M., Bilotta, E. M., Rutter, Z. J., Barta, P. A., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-025-02137-2 · Cited by 30 · see citing works
Self-citationIntrinsic signaling pathways modulate targeted protein degradation
Yuki, M., Akizuki, Y., Honda, R., Takao, M., Tsuchimoto, A., Hashimoto, S., Iio, H., Kato, M., Kaiho-Soma, A., Saeki, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49519-z · Cited by 29 · see citing works
Ege, N., Bouguenina, H., Tatari, M. N., & Chopra, R. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.02.011 · Cited by 30 · 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
Molecular glues: enhanced protein-protein interactions and cell proteome editing
Weagel, E. G., Foulks, J. M., Siddiqui, A. Q., & Warner, S. L. (2022) · Medicinal Chemistry Research · doi:10.1007/s00044-022-02882-2 · Cited by 29 · see citing works
Huang, Y., Yokoe, H., Kaiho-Soma, A., Takahashi, K., Hirasawa, Y., Morita, H., Ohtake, F., & Kanoh, N. (2021) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.1c00490 · Cited by 28 · see citing works
Activity-based profiling of cullin–RING E3 networks by conformation-specific probes
Henneberg, L. T., Singh, J., Duda, D. M., Baek, K., Yanishevski, D., Murray, P. J., Mann, M., Sidhu, S. S., & Schulman, B. A. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01392-5 · Cited by 31 · see citing works
Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?
Kuemper, S., Cairns, A. G., Birchall, K., Yao, Z., & Large, J. M. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1370509 · Cited by 27 · see citing works
Zhang, Y., Jost, M., Pak, R. A., Lu, D., Li, J., Lomenick, B., Garbis, S. D., Li, C.-M., Weissman, J. S., Lipford, J. R., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2205608119 · Cited by 23 · see citing works
Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizersPreprint
Poirson, J., Dhillon, A., Cho, H., Lam, M. H. Y., Alerasool, N., Lacoste, J., Mizan, L., & Taipale, M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.15.503206 · Cited by 24 · see citing works
Exploiting E3 ligases for lung cancer therapy: The promise of DCAF-PROTACs
Hussain, M. S., Eltaib, L., Rana, A. J., Maqbool, M., Ashique, S., Alanazi, M. N., Khan, Y., & Agrawal, M. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156001 · Cited by 22 · see citing works
CSN5A Subunit of COP9 Signalosome Temporally Buffers Response to Heat in Arabidopsis
Singh, A. K., Yadav, B. S., Dhanapal, S., Berliner, M., Finkelshtein, A., & Chamovitz, D. (2019) · Biomolecules · doi:10.3390/biom9120805 · Cited by 20 · see citing works
Monovalent protein-degraders – Insights and future perspectives
Cornella‐Taracido, I., & Garcı́a-Echeverrı́a, C. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127202 · Cited by 18 · see citing works
TRIP12 structures reveal HECT E3 formation of K29 linkages and branched ubiquitin chains
Maiwald, S. A., Schneider, L. A., Vollrath, R., Liwocha, J., Maletic, M. D., Swatek, K. N., Mulder, M. P. C., & Schulman, B. A. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01561-1 · Cited by 17 · see citing works
Proteolysis-targeting chimeras in biotherapeutics: Current trends and future applications
Li, Q., Zhou, L., Qin, S., Huang, Z., Li, B., Li, B., Yang, M., Nice, E. C., Zhu, H., & Huang, C. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115447 · Cited by 17 · see citing works
Development of the First-in-Class FEM1B-Recruiting Histone Deacetylase Degraders
Feller, F., Honin, I., Miranda, M., Weber, H. B., Henze, S., Hanl, M., & Hansen, F. K. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02569 · Cited by 19 · see citing works
HUWE1 Amplifies Ubiquitin Modifications to Broadly Stimulate Clearance of Proteins and AggregatesPreprint
Zhou, M., Fang, R., Colson, L., Donovan, K. A., Hunkeler, M., Song, Y., Zhang, C. M., Chen, S.-Y., Lee, D. H., Bradshaw, G. A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.30.542866 · Cited by 16 · see citing works
Quantitative analyses for effects of neddylation on CRL2VHL substrate ubiquitination and degradation
Wang, K., Reichermeier, K. M., & Liu, X. (2021) · Protein Science · doi:10.1002/pro.4176 · Cited by 16 · see citing works
Huang, Y., Gao, J., Ji, G., Li, W., Wang, J., Wang, Q., Shen, Y., Guo, J., & Gao, F. (2025) · The Plant Cell · doi:10.1093/plcell/koaf022 · Cited by 15 · see citing works
EFMC: Trends in Medicinal Chemistry and Chemical Biology
Auberson, Y. P., Arimondo, P. B., Duca, M., Essig, S., Grether, U., Rufer, A. C., Sbardella, G., Schopfer, U., Torrens, A., van der Stelt, M., et al. (2023) · ChemBioChem · doi:10.1002/cbic.202200690 · Cited by 16 · see citing works
Expanding the Degradable Proteome: Designing PROTACs by the Book
Jaeger, M. G., & Winter, G. E. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2019.12.009 · Cited by 14 · see citing works
Self-citationGenetic and compound screens uncover factors modulating cancer cell response to indisulam
Pogacar, Z., Groot, K., Jochems, F., Dias, M. D. S., Mulero‐Sánchez, A., Morris, B., Roosen, M. M., Wardak, L., Conti, G. D., Velds, A., et al. (2022) · Life Science Alliance · doi:10.26508/lsa.202101348 · Cited by 13 · see citing works
A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis
Nguyen, T., Lin, J.-M. G., Marques, A.-S. M. C., Fottner, M., Bauer, L. G., Reicher, A., Daum, D., Scrofani, L., Liu, Y., Cheng, C., et al. (2025) · Science · doi:10.1126/science.adv4257 · Cited by 14 · see citing works
Self-citationEmerging mechanisms of targeted protein degradation by molecular glues
Frere, G. A., de Araujo, E. D., & Gunning, P. T. (2022) · Methods in cell biology · doi:10.1016/bs.mcb.2022.01.001 · Cited by 12 · see citing works
Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs
Winter, G. E. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00191 · Cited by 12 · see citing works
Self-citationLi, X., Li, W., Zhang, Y., Xu, L., & Song, Y. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.101150 · Cited by 10 · see citing works
Kolossváry, I., & Sherman, W. (2023) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.3c02028 · Cited by 10 · see citing works
Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder
Park, S., Takwale, A. D., Lee, J., Yu, N., Kim, Y., Lee, J., Cho, Y. H., Cho, J. H., Moon, J. H., Lee, G. S., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117642 · Cited by 8 · see citing works
CSN5i-3 is an orthosteric molecular glue inhibitor of COP9 signalosome
Shi, H., Wang, X., Yu, C., Mao, H., Jiao, F., Braitbard, M., Shor, B., Zhang, Z., Hinds, T. R., Cao, S., et al. (2026) · Nature · doi:10.1038/s41586-026-10129-y · Cited by 8 · see citing works
New Frontiers in the Discovery and Development of PROTACs
Barghout, S. H. (2022) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520622666220412132759 · Cited by 8 · see citing works
Ciulli, A., & Hsia, O. (2022) · doi:10.1002/9781119774198.ch9 · Cited by 8 · see citing works
Beute für das Proteasom: Gezielter Proteinabbau aus medizinalchemischer Perspektive
Luh, L. M., Scheib, U., Juenemann, K., Wortmann, L., Brands, M., & Cromm, P. M. (2020) · Angewandte Chemie · doi:10.1002/ange.202004310 · Cited by 7 · see citing works
Molecular Glue Degraders: From Serendipity to Hunting and Design
Nieto‐Barrado, L., Domostegui, A., & Mayor‐Ruiz, C. (2022) · doi:10.1002/9783527836208.ch6 · Cited by 7 · see citing works
Self-citationIdentification of non-conventional small molecule degraders and stabilizers of squalene synthase
Hoock, J., Rossetti, C., Bilgin, M., Depta, L., Enemark‐Rasmussen, K., Christianson, J. C., & Laraia, L. (2023) · Chemical Science · doi:10.1039/d3sc04064j · Cited by 6 · see citing works
Wilson, J., & Loizou, J. I. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13272 · Cited by 6 · see citing works
Kalinichenko, A., Huemer, J., Humer, T., Haimel, M., Svatoň, M., Socquet-Juglard, N., Casoni, G. P., Prakash, C., von der Linde, M., Pázmándi, J., et al. (2025) · Science Immunology · doi:10.1126/sciimmunol.ado3825 · Cited by 5 · see citing works
Self-citationCAND1 inhibits Cullin-2-RING ubiquitin ligases for enhanced substrate specificity
Wang, K., Diaz, S., Li, L., Lohman, J. R., & Liu, X. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01167-5 · Cited by 5 · see citing works
Zhang, R., Zheng, Y., Xiang, F., & Zhou, J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116756 · Cited by 4 · see citing works
Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities
Ge, J., Hirosue, S., Castillon, L., Patel, S. A., Wesolowski, L., Dyas, A., Yong, C., de Haan, S., Drost, J., Stewart, G. D., et al. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00361-w · Cited by 3 · see citing works
Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems
Yao, T., Zhou, Z., Wang, G., Zhu, Z.-Y., & Li, X.-N. (2026) · Acta Pharmacologica Sinica · doi:10.1038/s41401-026-01853-2 · Cited by 3 · see citing works
Barbosa, B. M. G., Sfyaki, A., Rafael, S., José‐Duran, F., Pous, J., Sánchez, C., Perez‐Lopez, C., Vilanova, M., Cigler, M., Gay, M., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202316730 · Cited by 3 · see citing works
Self-citationTrivalent PROTACs Enhance Protein Degradation Through Cooperativity and AvidityPreprint
Imaide, S., Riching, K. M., Vetma, V., Whitworth, C., Hughes, S. J., Trainor, N. B., Mahan, S. D., Murphy, N., Chan, K.-H., Testa, A., et al. (2020) · ChemRxiv · doi:10.26434/chemrxiv.13218695.v1 · Cited by 3 · see citing works
Xiong, Y., Reinhardt, C. J., Nguyen, T., Hoffman, M. A., Simon, G. M., Melillo, B. N., & Cravatt, B. F. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.6c03985 · Cited by 2 · see citing works
The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer
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Barbosa, B. M. G., Sfyaki, A., Rafael, S., José‐Duran, F., Pous, J., Sánchez, C., Perez‐Lopez, C., Vilanova, M., Cigler, M., Gay, M., et al. (2023) · Angewandte Chemie · doi:10.1002/ange.202316730 · Cited by 2 · see citing works
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Henneberg, L. T., Singh, J., Duda, D. M., Baek, K., Yanishevski, D., Murray, P. J., Mann, M., Sidhu, S. S., & Schulman, B. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.14.524048 · Cited by 2 · see citing works
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Self-citationTargeted Protein Degradation: Methods and Prospects
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Self-citationTrivalent PROTACs Enhance Protein Degradation Through Cooperativity and AvidityPreprint
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- Authors
- Mayor-Ruiz, C., Jaeger, M. G., Bauer, S., Brand, M., Sin, C., Hanzl, A., Mueller, A. C., Menche, J., & Winter, G. E.
- Affiliations
- Austrian Academy of Sciences (AT)
- Corresponding author
- Winter, Georg E.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 75
- Issue
- 4
- Pages
- 849-858.e8
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2969906935
- Semantic Scholar
- df31420f88e6c9eccbb89b8c781063364c2d3d2b
- Cited by
- 119
- References
- 80
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 15 · 2023: 20 · 2022: 22 · 2021: 15 · 2020: 15 · 2019: 1
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Boehringer Ingelheim Fonds
- Österreichischen Akademie der Wissenschaften (EMBO-LTF ALTF 676-2017)
- Apex Foundation
- Medizinische Universität Wien
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- cullin-RING ligases, targeted protein degradation, small-molecule degraders, substrate receptor, COP9 signalosome, CAND1, drug resistance, CRISPR-Cas9 screen, proteolysis
- MeSH terms
- COP9 Signalosome Complex, Humans, Transcription Factors, Cullin Proteins, Proteolysis
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