Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

An, Sainan; Fu, Liwu

doi:10.1016/j.ebiom.2018.09.005

Cited by 377Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

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An, Sainan, Fu, Liwu·2018·EBioMedicine

DOI 10.1016/j.ebiom.2018.09.005PMC PMC6197674

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Abstract

There are several challenges towards the development and clinical use of small molecule inhibitors, which are currently the main type of targeted therapies towards intracellular proteins. PROteolysis-TArgeting Chimeras (PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported. In this review, we summarize the emerging characteristics of small-molecule PROTACs, such as inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors. In tumor xenografts, small-molecule PROTACs can significantly attenuate tumor progression. In addition, we also introduce recent developments of the PROTAC technology such as homo-PROTACs. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.

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Thalidomide binds to the E3 ligase substrate adapter Cereblon (CRBN) and has often been used as the E3 ligase-binding moiety in degraders.
“The small molecule thalidomide, which binds to the ubiquitously expressed E3 ligase substrate adapter Cereblon (CRBN), has often been used as the E3 ligase-binding moiety in degraders[11].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [11]

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Zhang, X., Lee, H. C., Shirazi, F., Baladandayuthapani, V., Lin, H. Y., Kuiatse, I., Wang, H., Jones, R. J., Berkova, Z., Singh, R., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0044-x · Cited by 84 · see citing works
Use of PROTACS as molecular probes of angiogenesis
Bargagna‐Mohan, P., Baek, S., Lee, H., Kim, K., & Mohan, R. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2005.04.008 · Cited by 70 · see citing works
Degradation of target protein in living cells by small-molecule proteolysis inducer
Zhang, D., Baek, S.-H., Ho, A., & Kim, K. (2003) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2003.11.042 · Cited by 64 · see citing works
Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer
Bradbury, R. H., Acton, D. G., Broadbent, N., Brooks, A. N., Carr, G. R., Hatter, G., Hayter, B. R., Hill, K. J., Howe, N. J., Jones, R. D. O., et al. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.02.056 · Cited by 56 · see citing works
Development of a Small Hybrid Molecule That Mediates Degradation of His-Tag Fused Proteins
Okitsu, K., Hattori, T., Misawa, T., Shoda, T., Kurihara, M., Naito, M., & Demizu, Y. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00413 · Cited by 28 · see citing works
Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation
Leiser, D., Pochon, B., Blank-Liss, W., Francica, P., Glück, A. A., Aebersold, D. M., Zimmer, Y., & Medová, M. (2014) · FEBS Letters · doi:10.1016/j.febslet.2013.12.025 · Cited by 28 · see citing works
Nature Biotechnology's academic spinouts of 2013
Bouchie, A. J., Allison, M., Webb, S., & DeFrancesco, L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2846 · Cited by 14 · see citing works

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Small molecules in targeted cancer therapy: advances, challenges, and future perspectives
Zhong, L., Li, Y., Xiong, L., Wang, W., Wu, M., Yuan, T., Yang, W. M., Tian, C., Miao, Z., Wang, T., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00572-w · Cited by 1,735 · see citing works
Exploring the next generation of antibody–drug conjugates
Tsuchikama, K., Anami, Y., Ha, S. Y. Y., & Yamazaki, C. M. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00850-2 · Cited by 659 · see citing works
PROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 651 · see citing works
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 514 · see citing works
Challenges and Opportunities in Cancer Drug Resistance
Ward, R. A., Fawell, S. E., Floc’h, N., Flemington, V., McKerrecher, D., & Smith, P. D. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00383 · Cited by 454 · see citing works
Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges
Edmondson, 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
An overview of PROTACs: a promising drug discovery paradigm
Zi, L., Hu, M., Yu, Y., Du, C., Zhou, H., Liu, C., Chen, Y., Fan, L., Ma, H., Gong, Y., et al. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00112-0 · Cited by 366 · see citing works
Degradation of proteins by PROTACs and other strategies
Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.08.001 · Cited by 335 · see citing works
The PROTAC technology in drug development
Zou, Y., Ma, D., & Wang, Y. (2019) · Cell Biochemistry and Function · doi:10.1002/cbf.3369 · Cited by 307 · see citing works
The PROTACtable genome
Schneider, M., Radoux, C. J., Hercules, A., Ochoa, D., Dunham, I., Zalmas, L.-P., Hessler, G., Ruf, S., Shanmugasundaram, V., Hann, M. M., et al. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00245-x · Cited by 273 · see citing works
Development of dual and selective degraders of cyclin-dependent kinases 4 and 6
Jiang, B., Wang, E. S., Donovan, K. A., Liang, Y., Fischer, E. S., Zhang, T., & Gray, N. S. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201901336 · Cited by 272 · see citing works
E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points
Bricelj, A., Steinebach, C., Kuchta, R. D., Gütschow, M., & Sosič, I. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.707317 · Cited by 226 · see citing works
Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands
Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., Xu, T., Wang, M., Yang, C., Chinnaswamy, K., Stuckey, J. A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01393 · Cited by 229 · see citing works
The role of ubiquitination and deubiquitination in tumor invasion and metastasis
Han, S., Wang, R., Zhang, Y., Li, X., Gan, Y., Gao, F., Rong, P., Wang, W., & Li, W. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.69411 · Cited by 215 · see citing works
Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019)
Sánchez-Martínez, C., Lallena, M. J., Sanfeliciano, S. G., & de Dios, A. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126637 · Cited by 200 · see citing works
New-generation advanced PROTACs as potential therapeutic agents in cancer therapy
Wang, C., Zhang, Y., Chen, W., Wu, Y., & Xing, D. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02024-9 · Cited by 192 · see citing works
Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader
Potjewyd, F., Turner, A. W., Beri, J., Rectenwald, J. M., Norris-Drouin, J. L., Cholensky, S. H., Margolis, D. M., Pearce, K. H., Herring, L. E., & James, L. I. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.006 · Cited by 179 · see citing works
Emerging strategies to overcome resistance to third-generation EGFR inhibitors
Shi, K., Wang, G., Pei, J., Zhang, J., Wang, J., Ouyang, L., Wang, Y., & Li, W. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01311-6 · Cited by 172 · see citing works
PROTACs– a game-changing technology
Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., ter Brake, F., Essa, K., & Dömling, A. S. S. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1659242 · Cited by 167 · see citing works
Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs
Girardini, M., Maniaci, C., Hughes, S. J., Testa, A., & Ciulli, A. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.02.048 · Cited by 157 · see citing works
The role of reversible and irreversible covalent chemistry in targeted protein degradation
Kiely‐Collins, H., Winter, G. E., & Bernardes, G. J. L. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.005 · Cited by 156 · see citing works
Developments of CRBN-based PROTACs as potential therapeutic agents
Wang, C., Zhang, Y., Wu, Y., & Xing, D. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113749 · Cited by 152 · 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
Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments
Jung, Y. J., Tweedie, D., Scerba, M. T., & Greig, N. H. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00313 · Cited by 154 · see citing works
Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer
Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., McEachern, D., Wang, Y., Metwally, H., Wang, L., Matvekas, A., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00882 · Cited by 170 · see citing works
Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo
Luo, T., Zheng, Q., Shao, L., Ma, T., Mao, L., & Wang, M. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202206277 · Cited by 136 · see citing works
Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling
You, I., Erickson, E. C., Donovan, K. A., Eleuteri, N. A., Fischer, E. S., Gray, N. S., & Toker, A. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.014 · Cited by 132 · see citing works
HECT E3 ubiquitin ligases – emerging insights into their biological roles and disease relevance
Wang, Y., Argiles-Castillo, D., Kane, E. I., Zhou, A., & Spratt, D. E. (2020) · Journal of Cell Science · doi:10.1242/jcs.228072 · Cited by 128 · see citing works
Bivalent Ligands for Protein Degradation in Drug Discovery
Scheepstra, M., Hekking, K. F. W., Hijfte, L. V., & Folmer, R. H. A. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.01.006 · Cited by 120 · see citing works
Strategies for designing proteolysis targeting chimaeras (PROTACs)
He, S., Dong, G., Cheng, J., Wu, Y., & Sheng, C. (2022) · Medicinal Research Reviews · doi:10.1002/med.21877 · Cited by 118 · see citing works
Novel CRBN-Recruiting Proteolysis-Targeting Chimeras as Degraders of Stimulator of Interferon Genes with In Vivo Anti-Inflammatory Efficacy
Liu, J., Yuan, L., Ruan, Y., Deng, B., Yang, Z., Ren, Y., Li, L., Liu, T., Zhao, H., Mai, R., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01948 · Cited by 117 · 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
Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
Yang, K., Wu, H., Zhang, Z., Leisten, E. D., Nie, X., Liu, B., Wen, Z., Zhang, J., Cunningham, M. D., & Tang, W. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00046 · Cited by 124 · see citing works
Quantitating Endosomal Escape of a Library of Polymers for mRNA Delivery
Jiang, Y., Qiao, L., Wang, Y., Xu, E., Ho, A. S. L., Singh, P., Wang, Y., Jiang, Z., Yang, F., Tietjen, G. T., et al. (2020) · Nano Letters · doi:10.1021/acs.nanolett.9b04426 · Cited by 110 · see citing works
Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins
Bond, A. G., Craigon, C., Chan, K.-H., Testa, A., Karapetsas, A., Fasimoye, R. Y., Macartney, T., Blow, J. J., Alessi, D. R., & Ciulli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01532 · Cited by 111 · see citing works
Targeted protein degradation directly engaging lysosomes or proteasomes
Kim, J., Byun, I., Kim, D. Y., Joh, H., Kim, H. J., & Lee, M. J. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00344b · Cited by 106 · see citing works
Discovery of potent small molecule PROTACs targeting mutant EGFR
Zhao, H., Yang, X., Lei, H., Xi, X.-X., Lu, S., Zhang, J., Xin, M., & Zhang, S. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112781 · Cited by 105 · see citing works
Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway
Zheng, Z., Zhu, S.-T., Cheng, H., Zhang, X., Cheng, G., Thu, P. M., Wang, S. P., Li, H., Ding, M., Qiang, L., et al. (2020) · Autophagy · doi:10.1080/15548627.2020.1757955 · Cited by 102 · see citing works
Bifunctional chemical probes inducing protein–protein interactions
Maniaci, C., & Ciulli, A. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.07.003 · Cited by 100 · see citing works
Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance
Lin, X., Xiang, H., & Luo, G. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112689 · Cited by 100 · see citing works
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins
Lin, J., Jin, J., Shen, Y., Zhang, L., Gong, G., Bian, H., Chen, H., Nagle, D. G., Wu, Y., Zhang, W., et al. (2021) · Theranostics · doi:10.7150/thno.62686 · Cited by 98 · see citing works
Novel immunomodulatory drugs and neo-substrates
Gao, S., Wang, S., & Song, Y. (2020) · Biomarker Research · doi:10.1186/s40364-020-0182-y · Cited by 95 · see citing works
Protein degradation technology: a strategic paradigm shift in drug discovery
Li, H., Dong, J., Cai, M., Xu, Z., Cheng, X., & Qin, J. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01146-7 · Cited by 94 · see citing works
Identification of a potent and selective covalent Pin1 inhibitor
Pinch, B. J., Doctor, Z. M., Nabet, B., Browne, C. M., Seo, H., Mohardt, M. L., Kozono, S., Lian, X., Manz, T. D., Chun, Y., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0550-9 · Cited by 90 · see citing works
Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer
Cimas, F. J., Niza, E., Juan, A., Noblejas‐López, M. D. M., Bravo, I., Lara‐Sánchez, A., Alonso‐Moreno, C., & Ocaña, A. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12100986 · Cited by 88 · see citing works
An overview of kinase downregulators and recent advances in discovery approaches
Wang, B., Wu, H., Hu, C., Wang, H., Liu, J., Wang, W., & Liu, Q. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00826-7 · Cited by 91 · see citing works
Proteolysis 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
Structural Insights into PROTAC-Mediated Degradation of Bcl-xL
Chung, C., Dai, H., Fernández, E., Tinworth, C. P., Churcher, I., Cryan, J., Denyer, J. C., Harling, J. D., Konopacka, A., Queisser, M. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00266 · Cited by 86 · see citing works
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
LaPlante, G., & Zhang, W. (2021) · Cancers · doi:10.3390/cancers13123079 · Cited by 82 · see citing works
Salt-Inducible Kinase inhibition suppresses acute myeloid leukemia progression in vivo.
Tarumoto, Y., Lin, S., Wang, J.-H., Milazzo, J. P., Xu, Y.-L., Lu, B., Yang, Z., Wei, Y.-L., Polyanskaya, S. A., Wunderlich, M., et al. (2019) · Blood · doi:10.1182/blood.2019001576 · Cited by 60 · see citing works
PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation
Syahputra, E. W., Lee, H., Cho, H. J., Park, H. J., Park, K., & Hwang, D. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17040501 · Cited by 82 · see citing works
Multiple Myeloma Therapy: Emerging Trends and Challenges
Dima, D., Jiang, D., Singh, D. J., Hasipek, M., Shah, H., Ullah, F., Khouri, J., Maciejewski, J. P., & Jha, B. K. (2022) · Cancers · doi:10.3390/cancers14174082 · Cited by 82 · see citing works
Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs)
Saraswat, A. L., Vartak, R., Hegazy, R. R., Patel, A., & Patel, K. R. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.103387 · Cited by 81 · see citing works
Autophagy in the cancer-immunity dialogue
Yamazaki, T., Pedro, J. M. B., Galluzzi, L., Kroemer, G., & Pietrocola, F. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.003 · Cited by 78 · see citing works
HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations
Du, Y., Chen, Y., Wang, Y., Chen, J., Lu, X., Zhang, L., Li, Y., Wang, Z., Ye, G., & Zhang, G. (2022) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0835 · Cited by 78 · see citing works
Recent Advances in PROTACs for Drug Targeted Protein Research
Yao, T., Xiao, H., Wang, H., & Xu, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810328 · Cited by 78 · 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 targeted protein degradation for metabolic diseases therapy
Zhou, Q., Xiao, H., Yang, F., Wang, Y., Li, P., & Zheng, Z. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106627 · Cited by 76 · see citing works
Assays and Technologies for Developing Proteolysis Targeting Chimera Degraders
Liu, X., Zhang, X., Lv, D., Yuan, Y., Zheng, G., & Zhou, D. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0073 · Cited by 73 · see citing works
Targeted protein degradation in vivo with Proteolysis Targeting Chimeras: Current status and future considerations
Watt, G. F., Scott‐Stevens, P., & Gaohua, L. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.02.005 · Cited by 72 · see citing works
Steering the antitumor drug discovery campaign towards structurally diverse indolines
Thakur, A., Singh, A., Kaur, N., Ojha, R., & Nepali, K. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103436 · Cited by 72 · see citing works
Two-Stage Strategy for Development of Proteolysis Targeting Chimeras and its Application for Estrogen Receptor Degraders
Roberts, B. L., Ma, Z., Gao, A., Leisten, E. D., Yin, D., Xu, W., & Tang, W. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00140 · Cited by 72 · see citing works
A suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands
Han, B. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014715 · Cited by 72 · see citing works
The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1
Ciccone, L., Shi, C., di Lorenzo, D., Van Baelen, A.-C., & Tonali, N. (2020) · Molecules · doi:10.3390/molecules25102439 · Cited by 69 · see citing works
Novel approaches for the rational design of PROTAC linkers
Zagidullin, A. A., Milyukov, V. A., Rizvanov, A. A., & Bulatov, E. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00023 · Cited by 70 · see citing works
Hematopoietic Progenitor Kinase 1 in Tumor Immunology: A Medicinal Chemistry Perspective
Zhu, Q., Chen, N., Tian, X., Zhou, Y.-L., You, Q., & Xu, X. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00172 · Cited by 70 · see citing works
Hydrophobic tag-based protein degradation: Development, opportunity and challenge
He, Q., Zhao, X., Wu, D., Jia, S., Liu, C., Cheng, Z., Huang, F., Chen, Y., Lu, T., & Lü, S. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115741 · Cited by 70 · see citing works
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 · see citing works
A Designed Small Molecule Inhibitor of a Non-Coding RNA Sensitizes HER2 Negative Cancers to Herceptin
Costales, M. G., Hoch, D. G., Abegg, D., Childs‐Disney, J. L., Velagapudi, S. P., Adibekian, A., & Disney, M. D. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.8b10558 · Cited by 69 · see citing works
VHL-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
PROTACs: A novel strategy for cancer drug discovery and development
Han, X., & Sun, Y. (2023) · MedComm · doi:10.1002/mco2.290 · Cited by 67 · see citing works
Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells
Otto, C., Schmidt, S., Kastner, C., Denk, S., Kettler, J., Müller, N., Germer, C., Wolf, E., Gallant, P., & Wiegering, A. (2019) · Neoplasia · doi:10.1016/j.neo.2019.10.003 · Cited by 68 · see citing works
MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment
Bartolucci, D., Montemurro, L., Raieli, S., Lampis, S., Pession, A., Hrelia, P., & Tonelli, R. (2022) · Cancers · doi:10.3390/cancers14184421 · Cited by 65 · see citing works
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 67 · see citing works
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 · see citing works
Cullin Ring Ubiquitin Ligases (CRLs) in Cancer: Responses to Ionizing Radiation (IR) Treatment
Fouad, S., Wells, O. S., Hill, M. A., & D’Angiolella, V. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01144 · Cited by 63 · see citing works
A Bioorthogonal Small Molecule Selective Polymeric “Clickase”
Chen, J., Li, K., Bonson, S. E., & Zimmerman, S. C. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c06553 · Cited by 63 · see citing works
DrugnomeAI is an ensemble machine-learning framework for predicting druggability of candidate drug targets
Raies, A. B., Tulodziecka, E., Stainer, J., Middleton, L., Dhindsa, R. S., Hill, P., Engkvist, O., Harper, A. R., Petrovski, S., & Vitsios, D. (2022) · Communications Biology · doi:10.1038/s42003-022-04245-4 · Cited by 62 · see citing works
Application of machine learning models for property prediction to targeted protein degraders
Peteani, G., Huynh, M. T. D., Gerebtzoff, G., & Rodríguez-Pérez, R. (2024) · Nature Communications · doi:10.1038/s41467-024-49979-3 · Cited by 61 · see citing works
Journey of PROTAC: From Bench to Clinical Trial and Beyond
Berkley, K., Zalejski, J., Sharma, N., & Sharma, A. K. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00577 · Cited by 62 · see citing works
Proteolysis targeting chimeras (PROTACs) for epigenetics research
Vogelmann, A., Robaa, D., Sippl, W., & Jung, M. (2020) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.01.010 · Cited by 59 · see citing works
Advances in targeted therapy for tumor with nanocarriers: A review
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Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope
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 57 · see citing works
Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design
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Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation
Xi, M., Chen, Y., Yang, H., Xu, H., Du, K., Wu, C., Xu, Y., Deng, L., Luo, X., Yu, L., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.04.036 · Cited by 56 · see citing works
Dual targeting of SREBP2 and ERRα by carnosic acid suppresses RANKL-mediated osteoclastogenesis and prevents ovariectomy-induced bone loss
Zheng, Z., Cheng, H., Zhou, Y., Zhu, S.-T., Thu, P. M., Li, H., Li, P., & Xu, X. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-019-0484-5 · Cited by 57 · 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
Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor
Hu, R., Wang, W., Yang, Y.-Y., Hu, X.-T., Wang, Q., Zuo, W., Xu, Y., Feng, Q., & Wang, N. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113922 · Cited by 53 · see citing works
Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and Polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells
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Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer
Chen, L., Han, L., Mao, S., Xu, P., Xu, X., Zhao, R., Wu, Z., Zhong, K. L., Yu, G., & Wang, X. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113307 · Cited by 51 · see citing works
SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines
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MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment
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Triazol: A Privileged Scaffold for Proteolysis Targeting Chimeras
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PROTAC technology for the treatment of Alzheimer’s disease: advances and perspectives
Inuzuka, H., Liu, J., Wei, W., & Rezaeian, A.-H. (2022) · Acta Materia Medica · doi:10.15212/amm-2021-0001 · Cited by 51 · see citing works
Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents
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Deciphering the mechanism of E3 ubiquitin ligases in plant responses to abiotic and biotic stresses and perspectives on PROTACs for crop resistance
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Discovery of pomalidomide-based PROTACs for selective degradation of histone deacetylase 8
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Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020)
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Advances in high‐resolution mass spectrometry applied to pharmaceuticals in 2020: A whole new age of information
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Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
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Recent Advances in Small Molecule PROTACs for the Treatment of Cancer
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Small-molecule PROTACs: Novel Agents for Cancer Therapy
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Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery
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Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation
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Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation
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Authors: An, S., & Fu, L.
Affiliations: Sun Yat-sen University Cancer Center (CN)
Sun Yat-sen University (CN)
Corresponding author: Fu, Liwu
ORCID: Fu, Liwu
Venue: EBioMedicine
Publisher: Elsevier BV
Published: 2018-10
Volume: 36
Pages: 553-562
ISSN: 2352-3964 (ISSN-L)
DOI: 10.1016/j.ebiom.2018.09.005
PMC: PMC6197674
OpenAlex: W2890850288
Cited by: 363
References: 75
Citations by year: 2026: 36 · 2025: 40 · 2024: 57 · 2023: 37 · 2022: 57 · 2021: 55 · 2020: 46 · 2019: 35
FWCI: 3.43
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: EBioMedicine (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: Natural Science Foundation of Guangdong Province (2016A030312014)
National Key Scientific Instrument and Equipment Development Projects of China (2018ZX09711002-003-011)
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: PROTACs, targeted protein degradation, ubiquitin-proteasome system, target selectivity, drug resistance, tumor xenografts, intracellular protein degradation, targeted therapy
MeSH terms: Animals, Antineoplastic Agents, Humans, Signal Transduction, Biomarkers, Proteasome Endopeptidase Complex, Small Molecule Libraries, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Proteolysis, Proteasome Inhibitors

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Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

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