Molecular glue degraders: exciting opportunities for novel drug discovery
Abstract
Introduction Molecular Glue Degraders (MGDs) is a concept that refers to a class of compounds that facilitate the interaction between two proteins or molecules within a cell. These compounds act as bridge that enhances specific Protein-Protein Interactions (PPIs). Over the past decade, this technology has gained attention as a potential strategy to target proteins that were traditionally considered undruggable using small molecules. Areas covered This review presents the concept of cellular homeostasis and the balance between protein synthesis and protein degradation. The concept of protein degradation is concerned with molecular glues, which form part of the broader field of Targeted Protein Degradation (TPD). Next, pharmacochemical strategies for the rational design of MGDs are detailed and illustrated by examples of Ligand-Based (LBDD), Structure-Based (SBDD) and Fragment-Based Drug Design (FBDD). Expert opinion Expanding the scope of what can be effectively targeted in the development of treatments for diseases that are incurable or resistant to conventional therapies offers new therapeutic options. The treatment of microbial infections and neurodegenerative diseases is a major societal challenge, and the discovery of MGDs appears to be a promising avenue. Combining different approaches to discover and exploit a variety of innovative therapeutic agents will create opportunities to treat diseases that are still incurable.
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Unlike conventional inhibitors, molecular glues facilitate protein degradation by inducing proximity between the target and E3 ligases and have gained attention as a potential strategy for targeting proteins.
“Unlike conventional inhibitors, molecular glues facilitate protein degradation by inducing proximity between the target and E3 ligases and have gained attention as a potential strategy for targeting proteins54,55.”
From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [54]
Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840 · see citing works
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 · see citing works
Adapting Proteostasis for Disease Intervention
Balch, W. E., Morimoto, R. I., Dillin, A., & Kelly, J. W. (2008) · Science · doi:10.1126/science.1141448 · Cited by 2,495 · see citing works
The JAZ family of repressors is the missing link in jasmonate signalling
Chini, A., Fonseca, S., Santos-Fernandez, G., Adie, B. A. T., Chico, J. M., Lorenzo, Ó., García‐Casado, G., López‐Vidriero, I., Lozano, F. M., Ponce, M. R., et al. (2007) · Nature · doi:10.1038/nature06006 · Cited by 2,426 · see citing works
Identification of a Primary Target of Thalidomide Teratogenicity
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., & Handa, H. (2010) · Science · doi:10.1126/science.1177319 · Cited by 2,136 · see citing works
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 · see citing works
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Arkin, M. R., & Wells, J. A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1343 · Cited by 1,705 · see citing works
Mechanism of auxin perception by the TIR1 ubiquitin ligase
Tan, X., Calderon-Villalobos, L. I. A., Sharon, M., Zheng, C., Robinson, C. V., Estelle, M., & Zheng, N. (2007) · Nature · doi:10.1038/nature05731 · Cited by 1,688 · see citing works
Protein Posttranslational Modifications: The Chemistry of Proteome Diversifications
Walsh, C. T., Garneau‐Tsodikova, S., & Gatto, G. J. J. (2005) · Angewandte Chemie International Edition · doi:10.1002/anie.200501023 · Cited by 1,609 · see citing works
The cell: a molecular approach
(1997) · Choice Reviews Online · doi:10.5860/choice.35-0264 · Cited by 1,465 · see citing works
Lysosome-targeting chimaeras for degradation of extracellular proteins
Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., & Bertozzi, C. R. (2020) · Nature · doi:10.1038/s41586-020-2545-9 · Cited by 1,199 · see citing works
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141 · see citing works
Hypoxia-Inducible Factor 1 (HIF-1) Pathway
Semenza, G. L. (2007) · Science s STKE · doi:10.1126/stke.4072007cm8 · Cited by 942 · see citing works
Proteome-wide covalent ligand discovery in native biological systems
Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., González-Páez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., et al. (2016) · Nature · doi:10.1038/nature18002 · Cited by 940 · cited 1× · see citing works
“Fragment screening is therefore an unique and powerful method to discover new E3 ligases and new ligands of E3 ligases that can be artificially exploited to design MGDs and degrade neosubstrates [93].”
BackgroundLi, W., Bengtson, M. H., Ulbrich, A., Matsuda, A., Reddy, V. A., Orth, A. P., Chanda, S. K., Batalov, S., & Joazeiro, C. A. P. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001487 · Cited by 839 · see citing works
Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15
Han, T., Goralski, M., Gaskill, N., Capota, E., Kim, J., Ting, T. C., Xie, Y., Williams, N. S., & Nijhawan, D. (2017) · Science · doi:10.1126/science.aal3755 · Cited by 762 · see citing works
A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
Matyskiela, M. E., Lu, G., Ito, T., Pagarigan, B., Lu, C.-C., Miller, K., Fang, W., Wang, N.-Y., Nguyen, D., Houston, J., et al. (2016) · Nature · doi:10.1038/nature18611 · Cited by 701 · see citing works
AUTACs: Cargo-Specific Degraders Using Selective Autophagy
Takahashi, D., Moriyama, J., Nakamura, T., Miki, E., Takahashi, E., Sato, A., Akaike, T., Itto-Nakama, K., & Arimoto, H. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.009 · Cited by 675 · see citing works
Erlanson, D. A., McDowell, R. S., & O'Brien, T. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm040031v · Cited by 645 · see citing works
Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase
Petzold, G., Fischer, E. S., & Thomä, N. H. (2016) · Nature · doi:10.1038/nature16979 · Cited by 620 · see citing works
Gandhi, A. K., Kang, J., Havens, C. G., Conklin, T., Ning, Y., Wu, L., Ito, T., Ando, H., Waldman, M. F., Thakurta, A., et al. (2014) · British Journal of Haematology · doi:10.1111/bjh.12708 · Cited by 619 · see citing works
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537 · cited 1× · see citing works
“The phthalimide (of thalidomide and pomalidomide) or isoin-dolinone (of lenalidomide) ring is exposed on the surface of the CRBN protein and alters the surface of the E3 ligase which is essential to interact with neosubstrates [23,32,33].”
BackgroundChamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531 · see citing works
Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins
Neklesa, T. K., Tae, H. S., Schneekloth, A. R., Stulberg, M. J., Corson, T. W., Sundberg, T. B., Raina, K., Holley, S. A., & Crews, C. M. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.597 · Cited by 429 · see citing works
Selective degradation of splicing factor CAPERα by anticancer sulfonamides
Uehara, T., Minoshima, Y., Sagane, K., Sugi, N. H., Mitsuhashi, K. O., Yamamoto, N., Kamiyama, H., Takahashi, K., Kotake, Y., Uesugi, M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2363 · Cited by 396 · 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
Immunophilin-sensitive protein phosphatase action in cell signaling pathways
Schreiber, S. L. (1992) · Cell · doi:10.1016/0092-8674(92)90158-9 · Cited by 344 · see citing works
Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening
Resnick, E., Bradley, A., Gan, J., Douangamath, A., Krojer, T., Sethi, R., Geurink, P. P., Aimon, A., Amitai, G., Bellini, D., et al. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b02822 · Cited by 335 · see citing works
PHOTACs enable optical control of protein degradation
Reynders, M., Matsuura, B. S., Bérouti, M., Simoneschi, D., Marzio, A., Pagano, M., & Trauner, D. H. (2020) · Science Advances · doi:10.1126/sciadv.aay5064 · Cited by 333 · see citing works
A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos
Matyskiela, M. E., Zhang, W., Man, H.-W., Muller, G., Khambatta, G., Baculi, F., Hickman, M., LeBrun, L., Pagarigan, B., Carmel, G., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01921 · Cited by 309 · see citing works
Getting into position: the catalytic mechanisms of protein ubiquitylation
Passmore, L. A., & Barford, D. (2004) · Biochemical Journal · doi:10.1042/bj20040198 · Cited by 305 · see citing works
Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic
Sasso, J. M., Tenchov, R., Wang, D.-S., Johnson, L. S., Wang, X., & Zhou, Q. A. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00245 · Cited by 259 · see citing works
Hughes, S. J., & Ciulli, A. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170041 · Cited by 240 · see citing works
Hansen, J. D., Correa, M., Nagy, M. A., Alexander, M., Plantevin, V., Grant, V., Whitefield, B., Huang, D., Kercher, T., Harris, R., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01928 · Cited by 240 · see citing works
Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15
Faust, T. B., Yoon, H., Nowak, R. P., Donovan, K. A., Li, Z., Cai, Q., Eleuteri, N. A., Zhang, T., Gray, N. S., & Fischer, E. S. (2020) · Nature Chemical Biology · doi:10.1038/s41589-019-0378-3 · Cited by 218 · see citing works
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction
Simonetta, K. R., Taygerly, J., Boyle, K., Basham, S. E., Padovani, C., Lou, Y., Cummins, T. J., Yung, S. L., von Soly, S. K., Kayser, F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09358-9 · Cited by 217 · see citing works
Small Molecule Targeted Recruitment of a Nuclease to RNA
Costales, M. G., Matsumoto, Y., Velagapudi, S. P., & Disney, M. D. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b01233 · Cited by 212 · see citing works
Hagner, P. R., Man, H.-W., Fontanillo, C., Wang, M., Couto, S., Breider, M., Bjorklund, C., Havens, C. G., Lu, G., Rychak, E., et al. (2015) · Blood · doi:10.1182/blood-2015-02-628669 · Cited by 203 · see citing works
Rational Chemical Design of Molecular Glue Degraders
Toriki, E. S., Papatzimas, J. W., Nishikawa, K., Dovala, D., Frank, A. O., Hesse, M. J., Danková, D., Song, J.-G., Bruce-Smythe, M., Struble, H., et al. (2023) · ACS Central Science · doi:10.1021/acscentsci.2c01317 · Cited by 196 · see citing works
BacPROTACs mediate targeted protein degradation in bacteria
Morreale, F. E., Kleine, S., Leodolter, J., Junker, S., Hoi, D. M., Ovchinnikov, S., Okun, A., Kley, J., Kurzbauer, R., Junk, L., et al. (2022) · Cell · doi:10.1016/j.cell.2022.05.009 · Cited by 196 · see citing works
The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron
Ichikawa, S., Flaxman, H. A., Xu, W., Vallavoju, N., Lloyd, H. C., Wang, B., Shen, D., Pratt, M. R., & Woo, C. M. (2022) · Nature · doi:10.1038/s41586-022-05333-5 · Cited by 195 · see citing works
Du, X., Volkov, O. A., Czerwinski, R. M., Tan, H., Huerta, C., Morton, E. R., Rizzi, J. P., Wehn, P. M., Xu, R., Nijhawan, D., et al. (2019) · Structure · doi:10.1016/j.str.2019.10.005 · Cited by 181 · see citing works
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation
Oleinikovas, V., Gainza, P., Ryckmans, T., Fasching, B., & Thomä, N. H. (2024) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022123-104147 · Cited by 178 · cited 1× · see citing works
“CELMoDs represent the first clinical examples of rationally designed MGDs [76].”
BackgroundAuxin Perception--Structural Insights
Calderon-Villalobos, L. I., Tan, X., Zheng, N., & Estelle, M. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005546 · Cited by 177 · see citing works
Haven't got a glue: Protein surface variation for the design of molecular glue degraders
Kozicka, Z., & Thomä, N. H. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2021.04.009 · Cited by 170 · see citing works
Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy
Bonazzi, S., d’Hennezel, E., Beckwith, R. E. J., Xu, L., Fazal, A., Magracheva, A., Ramesh, R., Cernijenko, A., Antonakos, B., Bhang, H.-E. C., et al. (2023) · Cell Chemical Biology · doi:10.1016/j.chembiol.2023.02.005 · Cited by 167 · see citing works
SNIPERs—Hijacking IAP activity to induce protein degradation
Naito, M., Ohoka, N., & Shibata, N. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2018.12.002 · Cited by 167 · see citing works
Hansen, J. D., Correa, M., Alexander, M., Nagy, M., Huang, D., Sapienza, J., Lu, G., LeBrun, L. A., Cathers, B. E., Zhang, W., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01489 · Cited by 159 · see citing works
Lenz, W., & Knapp, K. (1962) · Archives of Environmental Health An International Journal · doi:10.1080/00039896.1962.10663250 · Cited by 153 · see citing works
Reist, M., Carrupt, P., Francotte, E. R., & Testa, B. (1998) · Chemical Research in Toxicology · doi:10.1021/tx9801817 · Cited by 145 · see citing works
Heterobifunctional Molecules Induce Dephosphorylation of Kinases–A Proof of Concept Study
Yamazoe, S., Tom, J., Fu, Y., Wu, W., Zeng, L., Sun, C., Liu, Q., Lin, J. M., Lin, K., Fairbrother, W. J., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01167 · Cited by 145 · see citing works
Guharoy, M., Bhowmick, P., Sallam, M., & Tompa, P. (2016) · Nature Communications · doi:10.1038/ncomms10239 · Cited by 145 · see citing works
Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15
Ting, T. C., Goralski, M., Klein, K., Wang, B., Kim, J., Xie, Y., & Nijhawan, D. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.079 · Cited by 123 · see citing works
Strategies for developing DNA-encoded libraries beyond binding assays
Huang, Y., Li, Y., & Li, X. (2022) · Nature Chemistry · doi:10.1038/s41557-021-00877-x · Cited by 120 · see citing works
Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB
King, E. A., Cho, Y. J., Hsu, N. T., Dovala, D., McKenna, J. M., Tallarico, J. A., Schirle, M., & Nomura, D. K. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.02.008 · Cited by 104 · see citing works
Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide
Furihata, H., Yamanaka, S., Honda, T., Miyauchi, Y., Asano, A., Shibata, N., Tanokura, M., Sawasaki, T., & Miyakawa, T. (2020) · Nature Communications · doi:10.1038/s41467-020-18488-4 · Cited by 89 · see citing works
Selective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library
Powell, C. E., Du, G., Che, J., He, Z., Donovan, K. A., Yue, H., Wang, E. S., Nowak, R. P., Zhang, T., Fischer, E. S., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00520 · Cited by 88 · see citing works
Thalidomide mimics uridine binding to an aromatic cage in cereblon
Hartmann, M. D., Boichenko, I., Coles, M., Zanini, F., Lupas, A. N., & Hernandez Alvarez, B. (2014) · Journal of Structural Biology · doi:10.1016/j.jsb.2014.10.010 · Cited by 83 · see citing works
Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs
Gemechu, Y., Millrine, D., Hashimoto, S., Prakash, J., Sanchenkova, K., Metwally, H., Parajuli, G., Kang, S., & Kishimoto, T. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814446115 · Cited by 81 · see citing works
Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design
Jarusiewicz, J., Yoshimura, S., Mayasundari, A., Actis, M., Aggarwal, A., McGowan, K. M., Yang, L., Li, Y., Fu, X., Mishra, V., et al. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.2c00436 · Cited by 77 · see citing works
CRISPR Screen Reveals BRD2/4 Molecular Glue-like Degrader via Recruitment of DCAF16
Shergalis, A. G., Marin, V. L., Rhee, D. Y., Senaweera, S., McCloud, R. L., Ronau, J. A., Hutchins, C. W., McLoughlin, S. M., Woller, K. R., Warder, S. E., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.2c00747 · Cited by 76 · see citing works
Antiviral PROTACs: Opportunity borne with challenge
Liang, J., Wu, Y., Lan, K., Dong, C., Wu, S., Li, S., & Zhou, H. (2023) · Cell Insight · doi:10.1016/j.cellin.2023.100092 · Cited by 74 · see citing works
Bellenie, B. R., Cheung, K.-M. J., Varela, A., Pierrat, O. A., Collie, G. W., Box, G. M., Bright, M. D., Gowan, S., Hayes, A., Rodrigues, M. J., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02076 · Cited by 74 · see citing works
Disch, J. S., Duffy, J. M., Lee, E. C. Y., Gikunju, D., Chan, B., Levin, B. D., Monteiro, M. I., Talcott, S. A., Lau, A. C., Zhou, F., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00127 · Cited by 72 · see citing works
FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX
Ling, X., Xu, C., Fan, C., Zhong, K. L., Li, F., & Wang, X. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0683 · Cited by 70 · see citing works
Rational Screening for Cooperativity in Small-Molecule Inducers of Protein–Protein Associations
Liu, S., Tong, B., Mason, J. W., Ostrem, J. M. L., Tutter, A. V., Hua, B. K., Tang, S. A., Bonazzi, S., Briner, K., Berst, F., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c08307 · Cited by 69 · see citing works
A Double-Blind Study of the Sedative Effects of the Thalidomide Enantiomers in Humans
Höglund, P., Eriksson, T., & Björkman, S. E. (1998) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1023/a:1021008016719 · Cited by 67 · see citing works
Xie, H., Li, C., Tang, H., Tandon, I., Liao, J., Roberts, B. L., Zhao, Y. Q., & Tang, W. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01941 · Cited by 67 · see citing works
Fragment-based drug discovery supports drugging ‘undruggable’ protein–protein interactions
Wang, Z.-Z., Shi, X.-X., Huang, G.-Y., Hao, G., & Yang, G. (2023) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2023.01.008 · Cited by 64 · see citing works
Molecular glue concept solidifies
Baek, K., & Schulman, B. A. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0414-3 · Cited by 61 · see citing works
Wu, H., Yao, H., He, C., Jia, Y., Zhu, Z., Xu, S., Li, D., & Xu, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.019 · Cited by 60 · see citing works
Thalidomide: history, withdrawal, renaissance, and safety concerns
Vargesson, N., & Stephens, T. D. (2021) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2021.1991307 · Cited by 55 · see citing works
Recent Advances in PROTAC-Based Antiviral Strategies
Ahmad, H., Zia, B., Husain, H., & Husain, A. (2023) · Vaccines · doi:10.3390/vaccines11020270 · Cited by 54 · see citing works
Structural Aspects of Plant Hormone Signal Perception and Regulation by Ubiquitin Ligases
Tal, L., Gil, M. X. A., Guercio, A. M., & Shabek, N. (2020) · PLANT PHYSIOLOGY · doi:10.1104/pp.19.01282 · Cited by 53 · see citing works
A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
Xu, Y., Yu, Q., Wang, P., Wu, Z., Zhang, L., Wu, S., Li, M., Wu, B., Li, H., Zhuang, H., et al. (2022) · Advanced Science · doi:10.1002/advs.202104344 · Cited by 53 · see citing works
Identification and structural basis of C-terminal cyclic imides as natural degrons for cereblon
Heim, C., Spring, A.-K., Kirchgäßner, S., Schwarzer, D., & Hartmann, M. D. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.11.001 · Cited by 51 · see citing works
Michaelides, I. N., & Collie, G. W. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01882 · Cited by 50 · see citing works
Approaching Target Selectivity by De Novo Drug Design
Fischer, T., Gazzola, S., & Riedl, R. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1615435 · Cited by 46 · see citing works
Matyskiela, M. E., Zhu, J., Baughman, J. M., Clayton, T., Slade, M., Wong, H. K., Danga, K., Zheng, X., Labow, M., LeBrun, L. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00674 · Cited by 44 · 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
Recent advances in targeted protein degraders as potential therapeutic agents
Yang, N., Kong, B., Zhu, Z., Huang, F., Zhang, L., Lu, T., Chen, Y., Zhang, Y., & Jiang, Y. (2023) · Molecular Diversity · doi:10.1007/s11030-023-10606-w · Cited by 41 · see citing works
Chang, Y., Keramatnia, F., Ghate, P. S., Nishiguchi, G., Gao, Q., Iacobucci, I., Yang, L., Chepyala, D., Mishra, A., High, A. A., et al. (2023) · Blood · doi:10.1182/blood.2022017813 · Cited by 41 · see citing works
Okada, Y., Murayama, N., Yanagida, C., Shimizu, M., Guengerich, F. P., & Yamazaki, H. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.024679 · Cited by 41 · see citing works
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- Authors
- Lemaitre, T., Cornu, M., Schwalen, F., Since, M., Kieffer, C., & Voisin-Chiret, A. S.
- Affiliations
- Normandie Université (FR)
- Normandie University, UNICAEN, CERMN, Caen, France
- ORCID
- Venue
- Expert Opinion on Drug Discovery
- Publisher
- Informa UK Limited
- Published
- 2024-01-24
- Volume
- 19
- Issue
- 4
- Pages
- 433-449
- ISSN
- 1746-0441 (ISSN-L)
- 1746-045X
- OpenAlex
- W4391029468
- Cited by
- 36
- References
- 101
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 5
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- No funding
- 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
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- molecular glues, targeted protein degradation, protein-protein interaction, undruggable proteins, protein degradation, cellular homeostasis, ligand-based drug design, structure-based drug design, fragment-based drug discovery, rational drug design, microbial infection, neurodegenerative diseases
- MeSH terms
- Humans, Technology, Drug Design, Drug Discovery, Proteolysis
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