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Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Open accessAbstract
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors.
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In the citing paper
“However, possible off-target effects may arise from the E3 ligase ligand side, such as the degradation of GSPT1 in this work and others[42–44].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [42]
In the citing paper
“In addition, Bondeson et al. showed that a promiscuous ligand for about 50 kinases could induce only a subset of its targets for degradation when converted into a PROTAC45.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [45]
In the citing paper
“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [65]
In the citing paper
“Multiple studies have reported that the stability of the E3-degrader-POI ternary complex may influence degradation kinetics and selectivity, and may be a more reliable predictor for degradation than target engagement alone (Bondeson et al., 2018; Roy et al., 2019).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Bondeson et al., 2018
In the citing paper
“The propensity of different E3 ligases to ubiquitinate specific proteins has been reported to vary in the literature (Bondeson et al., 2018; Smith et al., 2019) and variation is attributed to the unique protein-protein interactions that may form between the E3 ligase and target.”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Bondeson et al., 2018
In the citing paper
“PROTACs are small molecules with two functional ends, wherein one end binds to the protein of interest while the other binds to an E3 ubiquitin ligase (2, 3), bringing the ubiquitin ligase to the target protein, leading to its ubiquitination and subsequent degradation by the proteasome.”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [2]
In the citing paper
“Addition of a linker with a moiety to recruit either VHL or CRBN reduced foretinib’s inhibition for several of these kinases, but overall both PROTACs retained broad non-selective inhibition.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“It has been shown that a PROTAC’s ability to bind the target protein is not the primary determinant of whether efficient degradation occurs; rather, it has been suggested that formation of the ternary complex is limiting (i.e., the ability of the PROTAC to simultaneously bind both the target protein and the E3 ligase) 20, 22.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“Moreover, the extent to which different kinases were degraded was not simply a reflection related to how tightly the PROTAC bound the kinase, since inhibition constants were not correlated with cellular degradation 20.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“Using a competitive binding assay, foretinib itself was first shown to inhibit at least a quarter of the human kinome 20.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“Remarkably, however, cellular treatment revealed that certain kinases were degraded much more efficiently by the VHL-recruiting PROTAC, while others were degraded more efficiently by the CRBN-recruiting PROTAC 20.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“It has further been shown that PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker 20, 23, 24, 33”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“PROTACs may also benefit from cooperative PPIs between the E3 ligase and the POI. This can have the advantages of improved potency49 and selectivity50.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [49]
In the citing paper
“the pairing of VHL versus CRBN for a given target can result in different degradation efficiencies49, as was first observed when targeting the fusion oncogene BCR–ABL by PROTACs118.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [49]
In the citing paper
“In addition, many PROTACs are not completely selective and can degrade proteins other than their desired targets [7, 90, 204, 205].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [204]
In the citing paper
“A major advantage of VHL-based PROTACs is their target-specificity [44, 53].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [53]
In the citing paper
“high binary binding affinities are not necessarily needed to result in efficient degradation of a target protein [53]”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [53]
In the citing paper
“using the same promiscuous kinase inhibitor as a warhead, the CRBN-based PROTAC degrades more kinases than the VHL-based PROTAC [53].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [53]
In the citing paper
“and several PROTACs have been found to be more selective than the inhibitor from which they were derived 12,28,29,30 ,”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [12]
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Citations
Cites
Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305
RING Domain E3 Ubiquitin Ligases
Deshaies, R. J., & Joazeiro, C. A. P. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.101807.093809 · Cited by 2,679
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609
Self-citationA quantitative analysis of kinase inhibitor selectivity
Karaman, M. W., Herrgard, S., Treiber, D. K., Gallant, P., Atteridge, C. E., Campbell, B. T., Chan, K. W., Ciceri, P., Davis, M. I., Edeen, P. T., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1358 · Cited by 2,466
A small molecule–kinase interaction map for clinical kinase inhibitors
Fabian, M. A., Biggs, W., Treiber, D. K., Atteridge, C. E., Azimioara, M. D., Benedetti, M. G., Carter, T. A., Ciceri, P., Edeen, P. T., Floyd, M. B., et al. (2005) · Nature Biotechnology · doi:10.1038/nbt1068 · Cited by 1,923
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879
Borst, O., Walker, B., Münzer, P., Russo, A., Schmid, E., Faggio, C., Bigalke, B., Laufer, S., Gawaz, M., & Lang, F. J. W. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350110 · Cited by 1,867
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., Wong, K.-K., Bradner, J. E., & Kaelin, W. G. (2014) · Science · doi:10.1126/science.1244917 · Cited by 1,583
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
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Items 201–300 of 965
Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs
Anderson, N. A., Cryan, J., Ahmed, A., Dai, H., McGonagle, G. A., Rozier, C., & Benowitz, A. B. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127106 · Cited by 69
A novel strategy to block mitotic progression for targeted therapy
Chi, J. J., Li, H., Zhou, Z., Izquierdo-Ferrer, J., Xue, Y., Wavelet, C. M., Schiltz, G. E., Zhang, B., Cristofanilli, M., Lu, X., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.10.013 · Cited by 68
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Wu, Y., Yang, Y., Wang, W., Sun, D., Zheng, M., Zhou, Y., Li, H., Zhu, M., Li, H., & Chen, L. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.07.007 · Cited by 67
PROTACs: A novel strategy for cancer drug discovery and development
Han, X., & Sun, Y. (2023) · MedComm · doi:10.1002/mco2.290 · Cited by 69
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 70
Monitoring and deciphering protein degradation pathways inside cells
Daniels, D. L., Riching, K. M., & Urh, M. (2018) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2018.12.001 · Cited by 65
Targeting androgen receptor degradation with PROTACs from bench to bedside
Jia, X., & Han, X. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114112 · Cited by 68
Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader
Wei, J., Hu, J., Wang, L., Xie, L., Jin, M. S., Chen, X., Liu, J., & Jin, J. J. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01528 · Cited by 67
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 66
Applications of covalent chemistry in targeted protein degradation
Lu, D., Yu, X., Lin, H., Cheng, R., Monroy, E. Y., Qi, X., Wang, M. C., & Wang, J. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00362g · Cited by 69
Self-citationTargeted protein degradation in cancers: Orthodox PROTACs and beyond
Li, J., Chen, X., Lü, A., & Liang, C. (2023) · The Innovation · doi:10.1016/j.xinn.2023.100413 · Cited by 68
Strategies to Target ISG15 and USP18 Toward Therapeutic Applications
Fernandez, D. J., Hess, S., & Knobeloch, K. (2020) · Frontiers in Chemistry · doi:10.3389/fchem.2019.00923 · Cited by 65
Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries
Wang, B., Liu, J., Tandon, I., Wu, S., Teng, P., Liao, J., & Tang, W. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113425 · Cited by 67
Emerging drug development technologies targeting ubiquitination for cancer therapeutics
Veggiani, G., Gerpe, M. C. R., Sidhu, S. S., & Zhang, W. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.03.003 · Cited by 67
Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery
Pei, H., Peng, Y., Zhao, Q., & Chen, Y. (2019) · RSC Advances · doi:10.1039/c9ra03423d · Cited by 70
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Han, X., Chen, L., Wei, Y., Yu, W., Chen, Y., Zhang, C., Jiao, B., Shi, T., Sun, L., Zhang, C., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02083 · Cited by 64
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Sathe, G. J., & Sapkota, G. P. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.08.007 · Cited by 68
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Pei, Y., Fu, J., Shi, Y., Zhang, M., Luo, G., Luo, X., Song, N., Mi, T., Yang, Y., Li, J. X., et al. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202204395 · Cited by 68
Li, W., Zhang, J., Guo, L., & Wang, Q. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c01150 · Cited by 63
Wang, R., Ascanelli, C., Abdelbaki, A., Fung, A., Rasmusson, T., Michaelides, I. N., Roberts, K., & Lindon, C. (2021) · Communications Biology · doi:10.1038/s42003-021-02158-2 · Cited by 64
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Baek, K., Metivier, R. J., Burman, S. S. R., Bushman, J. W., Yoon, H., Lumpkin, R. J., Ryan, J. K., Abeja, D. M., Lakshminarayan, M., Yue, H., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62099-w · Cited by 77
Zhang, H., Xie, R., AI-furas, H., Li, Y., Wu, Q., Li, J., Xu, F., & Xu, T. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00645 · Cited by 60
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Behl, T., Kumar, S., Althafar, Z. M., Sehgal, A., Singh, S., Sharma, N., Badavath, V. N., Yadav, S., Bhatia, S., Al‐Harrasi, A., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02851-1 · Cited by 65
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Ignatov, M., Jindal, A., Kotelnikov, S., Beglov, D., Posternak, G., Tang, X., Maisonneuve, P., Poda, G. I., Batey, R. A., Sicheri, F., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c09387 · Cited by 59
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Xu, L., Xu, B., Wang, J., Gao, Y., He, X., Xie, T., & Ye, X. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114900 · Cited by 62
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Eron, S. J., Huang, H., Agafonov, R. V., Fitzgerald, M. E., Patel, J., Michael, R. E., Lee, T. D., Hart, A. A., Shaulsky, J., Nasveschuk, C. G., et al. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00376 · Cited by 57
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Ma, S., Ji, J., Tong, Y., Zhu, Y., Dou, J., Zhang, X., Xu, S., Zhu, T., Xu, X., You, Q., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.02.022 · Cited by 59
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Nayak, D., Lv, D., Yuan, Y., Zhang, P., Hu, W., Nayak, A., Ruben, E. A., Lv, Z., Sung, P., Hromas, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46922-4 · Cited by 61
Molecular design opportunities presented by solvent‐exposed regions of target proteins
Jiang, X., Yu, J. H., Zhou, Z., Kongsted, J., Song, Y., Pannecouque, C. C., Clercq, E. D., Kang, D., Poongavanam, V., Liu, X., et al. (2019) · Medicinal Research Reviews · doi:10.1002/med.21581 · Cited by 57
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Fletcher, A., Clift, D., de Vries, E., Cuesta, S. M., Malcolm, T., Meghini, F., Chaerkady, R., Wang, J., Chiang, A. J., Weng, S. H. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42546-2 · Cited by 60
Self-citationWang, J., Ishchenko, A., Zhang, W., Razavi, A., & Langley, D. (2022) · Scientific Reports · doi:10.1038/s41598-022-05875-8 · Cited by 55
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Burslem, G. M., Ottis, P., Jaime‐Figueroa, S., Morgan, A. R., Cromm, P. M., Toure, M., & Crews, C. M. (2018) · ChemMedChem · doi:10.1002/cmdc.201800271 · Cited by 54
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Xia, L., Ba, M.-Y., Liu, W., Cheng, W., Hu, C.-P., Zhao, Q., Yao, Y., Sun, M., & Duan, Y. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0159 · Cited by 51
Haid, R. T. U., & Reichel, A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15010195 · Cited by 49
Annual review of KRAS inhibitors in 2022
Wang, H., Chi, L., Yu, F., Dai, H., Gao, C., Si, X., Wang, Z., Liu, L., Zheng, J., Shan, L., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115124 · Cited by 53
Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer
Wang, C., Wang, H., Zheng, C., Liu, Z., Gao, X., Xu, F., Niu, Y., Zhang, L., & Xu, P. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113386 · Cited by 49
Maksoud, S. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02339-4 · Cited by 48
Rapid and specific degradation of endogenous proteins in mouse models using auxin-inducible degrons
Macdonald, L., Taylor, G. C. A., Brisbane, J. M., Christodoulou, E., Scott, L., von Kriegsheim, A., Rossant, J., Gu, B., & Wood, A. J. (2022) · eLife · doi:10.7554/elife.77987 · Cited by 42
Ward, J. A., Perez‐Lopez, C., & Mayor‐Ruiz, C. (2023) · ChemBioChem · doi:10.1002/cbic.202300163 · Cited by 48
The 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 49
Venkatesan, J., Murugan, D., Lakshminarayanan, K., Smith, A. R., Thirumalaiswamy, H. V., Kandhasamy, H., Zender, B., Zheng, G., & Rangasamy, L. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108725 · Cited by 48
Riching, K. M., Schwinn, M. K., Vasta, J. D., Robers, M. B., Machleidt, T., Urh, M., & Daniels, D. L. (2020) · SLAS DISCOVERY · doi:10.1177/2472555220973602 · Cited by 46
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Nowak, R. P., & Jones, L. H. (2020) · SLAS DISCOVERY · doi:10.1177/2472555220979584 · Cited by 48
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Gopalsamy, A. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00397 · Cited by 45
Ha, S., Luo, G., & Xiang, H. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01487 · Cited by 48
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Singh, S., Tian, W., Severance, Z. C., Chaudhary, S. K., Anokhina, V. S., Mondal, B., Pergu, R., Singh, P. R., Dhawa, U., Singha, S., et al. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00943a · Cited by 47
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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 44
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Jostes, S., Nettersheim, D., & Schorle, H. (2019) · Nature Reviews Urology · doi:10.1038/s41585-019-0154-x · Cited by 45
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Ma, L., Li, Y., Luo, R., Wang, Y., Cao, J., Fu, W., Qian, B., Zheng, L., Tang, L., Lv, X., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00150 · Cited by 44
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Berlin, M. Y., Cantley, J. L., Bookbinder, M., Bortolon, E., Broccatelli, F., Cadelina, G., Chan, E. W., Chen, H., Chen, X., Cheng, Y., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01781 · Cited by 43
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Řezníčková, E., Krajčovičová, S., Peřina, M., Kovalová, M., Soural, M., & Kryštof, V. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114792 · Cited by 43
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Chen, H., Nguyen, N. H., Magtoto, C. M., Cobbold, S. A., Bidgood, G. M., Guzman, L. G. M., Richardson, L. W., Corbin, J. E., Au, A. E., Lechtenberg, B. C., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102552 · Cited by 42
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Lu, Y., Yang, Y., Zhu, G., Zeng, H., Fan, Y., Guo, F., Xu, D., Wang, B., Chen, D., & Ge, G. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.83026 · Cited by 42
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Dong, J., Ma, F., Cai, M., Cao, F., Li, H., Liang, H., Li, Y., Ding, G., Li, J., Cheng, X., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01518 · Cited by 43
Béry, N., Keller, L., Soulié, M., Gence, R., Iscache, A.-L., Cherier, J., Cabantous, S., Sordet, O., Lajoie‐Mazenc, I., Pédelacq, J. D., et al. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.08.009 · Cited by 41
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Rana, S., Mallareddy, J. R., Singh, S., Boghean, L., & Natarajan, A. (2021) · Cancers · doi:10.3390/cancers13215506 · Cited by 43
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Self-citationSTAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers
van der Lelij, P., Newman, J. A., Lieb, S., Jude, J., Katis, V. L., Hoffmann, T., Hinterndorfer, M., Bader, G., Kraut, N., Pearson, M. A., et al. (2020) · Life Science Alliance · doi:10.26508/lsa.202000725 · Cited by 40
Li, P., Jia, C., Fan, Z., Hu, X., Zhang, W., Liu, K., Sun, S., Guo, H., Yang, N., Zhu, M., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.01.014 · Cited by 39
Yang, N., Fan, Z., Sun, S., Hu, X., Mao, Y., Jia, C., Cai, X., Xu, T., Li, B., Li, Y., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115857 · Cited by 40
Yu, Y., Hu, W., Xu, Y., Xu, H.-B., & Gao, J.-Q. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113719 · Cited by 44
Chemical Protein Degradation Approach and its Application to Epigenetic Targets
Itoh, Y. (2018) · The Chemical Record · doi:10.1002/tcr.201800032 · Cited by 41
Bemis, T. A., Clair, J. J. L., & Burkart, M. D. (2020) · Chemical Communications · doi:10.1039/d0cc05395c · Cited by 37
Maneiro, M., Vita, E. D., Conole, D., Kounde, C. S., Zhang, Q., & Tate, E. W. (2021) · Progress in medicinal chemistry · doi:10.1016/bs.pmch.2021.01.002 · Cited by 38
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Fan, G., Chen, S., Zhang, Q., Yu, N., Shen, Z., Liu, Z., Guo, W., Tang, Z., Yang, J., & Liu, M. (2025) · MedComm · doi:10.1002/mco2.70401 · Cited by 48
Synthesis of 7-benzylguanosine cap-analogue conjugates for eIF4E targeted degradation
Kaur, T., Menon, A., & Garner, A. L. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.01.080 · Cited by 38
Metadata
- Authors
- Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M.
- Affiliations
- Yale University (US)
- Arvinas (United States) (US)
- Corresponding author
- Crews, Craig M.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 25
- Issue
- 1
- Pages
- 78-87.e5
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5777153
- OpenAlex
- W2767856718
- Cited by
- 923
- References
- 50
- Citations by year
- 2026: 104 · 2025: 133 · 2024: 147 · 2023: 104 · 2022: 110 · 2021: 110 · 2020: 109 · 2019: 72 · 2018: 29
- FWCI
- 23.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (F99 CA212229-02, R50 CA211252-02)
- Leukemia and Lymphoma Society Career Development
- NIH (R35CA197589)
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- PROTACs, protein degradation, E3 ubiquitin ligase, cereblon, VHL, protein-protein interaction, ternary complex stability, PROTAC design, undruggable proteins, ubiquitination, proteasome
- MeSH terms
- Humans, Drug Design, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Small Molecule Libraries, Ubiquitination, Proteolysis
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