PROTACs: A novel strategy for cancer therapy

Liu, Jing; Ma, Jia; Liu, Yi; Xia, Jun; Li, Yuyun; Wang, Z. Peter; Wei, Wenyi

doi:10.1016/j.semcancer.2020.02.006

Cited by 193Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

PROTACs: A novel strategy for cancer therapy

Liu, Jing, Ma, Jia, Liu, Yi, Xia, Jun, Li, Yuyun, Wang, Z. Peter, Wei, Wenyi·2020·Seminars in Cancer Biology

DOI 10.1016/j.semcancer.2020.02.006

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Abstract

Chemotherapeutic strategy has been widely used for treating malignance by targeting irregular expressed or mutant proteins with small molecular inhibitors (SMIs) or monoclonal antibodies (mAbs). However, most intracellular proteins lack of active sites or antigens where SMIs or mAbs bind with, and are called as non-druggable targets for a long time. From the first year of this century, PROteolysis-TArgeting Chimeras (PROTACs) has emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. The first generation of peptide-based PROTACs adopts β-TrCP and VHL as E3 ligases, but the cellular permeability and chemical stability issues restrict their clinical application. The second generation of small molecule-based PROTACs adopts MDM2, VHL, IAPs and Cereblon as E3 ligases have been tensely studied. To date, the targets of PROTACs including those overexpressed oncogenic proteins such as ER, AR and BRDs, disease-relevant fusion proteins such as NPM/EML4-ALK and BCR-ABL, cancer-driven mutant proteins such as EGFR, kinases such as CDKs and RTKs. The major disadvantage of PROTACs is the noncancer specificity and relative higher toxicity, due to its catalytic role. To overcome this, we and other have recently developed several similar light-controllable PROTACs, termed as the third generation controllable PROTACs. The degradation of targets by those PROTACs can be triggered by UVA or visible light, providing a tool box for further PROTACs design. Here in this review, we introduce the historical milestones and prospective for further PROTACs development in clinical use.

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PROTACs have several advantages over SMIs.
“As discussed above, PROTACs have several advantages over SMIs [32].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [32]

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Psoralen photobiology and photochemotherapy: 50 years of science and medicine
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Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer
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Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders
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PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding
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Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach
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Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs
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Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation
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Cellular Resistance Mechanisms to Targeted Protein Degradation Converge Toward Impairment of the Engaged Ubiquitin Transfer Pathway
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Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas
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Photodynamic Therapy of Non–Small Cell Lung Cancer. Narrative Review and Future Directions
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Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands
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3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation
Testa, A., Lucas, X., Castro, G. V., Chan, K.-H., Wright, J. E., Runcie, A. C., Gadd, M. S., Harrison, W. T. A., Ko, E. J., Fletcher, D., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b05807 · Cited by 144 · see citing works
Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity
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A caged E3 ligase ligand for PROTAC-mediated protein degradation with light
Kounde, C. S., Shchepinova, M. M., Saunders, C. N., Muelbaier, M., Rackham, M. D., Harling, J. D., & Tate, E. W. (2020) · Chemical Communications · doi:10.1039/d0cc00523a · Cited by 136 · see citing works
Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
Zhao, Q., Ren, C., Liu, L., Chen, J., Shao, Y., Sun, N., Sun, R., Kong, Y., Ding, X., Zhang, X., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01264 · Cited by 134 · see citing works
Development of hybrid small molecules that induce degradation of estrogen receptor‐alpha and necrotic cell death in breast cancer cells
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Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC)
Kang, C. H., Lee, D.-H., Lee, C. O., Ha, J. D., Park, C. H., & Hwang, J. Y. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.09.169 · Cited by 126 · see citing works
Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand
Demizu, Y., Shibata, N., Hattori, T., Ohoka, N., Motoi, H., Misawa, T., Shoda, T., Naito, M., & Kurihara, M. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.09.041 · Cited by 125 · see citing works
Development of Stabilized Peptide-Based PROTACs against Estrogen Receptor α
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Safety and Tolerability of Antibody-Drug Conjugates in Cancer
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Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein
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Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation
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Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation
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Development of protein degradation inducers of oncogenic BCR ‐ ABL protein by conjugation of ABL kinase inhibitors and IAP ligands
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PROTAC-mediated crosstalk between E3 ligases
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Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
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Targeting Nuclear Receptors with PROTAC degraders
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Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader
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Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor‐Targeting PROTACs
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Approved and Experimental Small‐Molecule Oncology Kinase Inhibitor Drugs: A Mid‐2016 Overview
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New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation
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Targeted Degradation of MDM2 as a New Approach to Improve the Efficacy of MDM2-p53 Inhibitors
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A novel cereblon modulator for targeted protein degradation
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A novel strategy to block mitotic progression for targeted therapy
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Different Degradation Mechanisms of Inhibitor of Apoptosis Proteins (IAPs) by the Specific and Nongenetic IAP-Dependent Protein Eraser (SNIPER)
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Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules
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SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib
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Corneal Cross-Linking (CXL): Standardizing Terminology and Protocol Nomenclature
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Kinase Inhibitor Conjugates
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PHOTACs Enable Optical Control of Protein Degradation
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Targeted protein degradation: mechanisms, strategies and application
Zhao, L., Zhao, J., Zhong, K., Tong, A., & Jia, D. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00966-4 · Cited by 986 · see citing works
Current strategies for the design of PROTAC linkers: a critical review
Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424 · see citing works
Cell cycle on the crossroad of tumorigenesis and cancer therapy
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PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy
Qi, S., Dong, J., Xu, Z., Cheng, X., Zhang, W., & Qin, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.692574 · Cited by 299 · see citing works
Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges
Zeng, S., Huang, W., Zheng, X., Cheng, L., Zhang, Z., Wang, J., & Shen, Z. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112981 · Cited by 262 · see citing works
TF-PROTACs Enable Targeted Degradation of Transcription Factors
Liu, J., Chen, H., Kaniskan, H. Ü., Xie, L., Chen, X., Jin, J., & Wei, W. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c03852 · Cited by 247 · see citing works
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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
A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity
Zhang, X., Qin-Ma, Wu, H.-P., Khamis, M. Y., Li, Y., Ma, L., & Liu, H. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01782 · Cited by 160 · see citing works
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Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications
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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
Development of hypoxia-activated PROTAC exerting a more potent effect in tumor hypoxia than in normoxia
Cheng, W., Li, S., Wen, X., Han, S., Wang, S., Han, W., Song, Z., Wang, Y., Tian, X., & Zhang, X. (2021) · Chemical Communications · doi:10.1039/d1cc05715d · Cited by 129 · see citing works
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00924-z · Cited by 126 · see citing works
Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression
Wang, K., Dai, X., Yu, A., Feng, C., Liu, K., & Huang, L. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02483-2 · Cited by 115 · see citing works
BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia
Amarante-Mendes, G. P., Rana, A., Datoguia, T. S., Hamerschlak, N., & Brumatti, G. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14010215 · Cited by 111 · see citing works
Discovery of potent small molecule PROTACs targeting mutant EGFR
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Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy
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Protein degradation technology: a strategic paradigm shift in drug discovery
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Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
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p53/MDM2 signaling pathway in aging, senescence and tumorigenesis
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Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer
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G-Quadruplex-Binding Proteins: Promising Targets for Drug Design
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PROTACs and Other Chemical Protein Degradation Technologies for the Treatment of Neurodegenerative Disorders
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Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
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Post-translational regulations of PD-L1 and PD-1: Mechanisms and opportunities for combined immunotherapy
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Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review
Zheng, J., Zhang, W., Li, L., He, Y., Wei, Y., Dang, Y., Nie, S., & Guo, Z. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.860985 · Cited by 79 · see citing works
Autophagy in the cancer-immunity dialogue
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Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression
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A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer
Li, G., Lin, S., Yu, Z., Wu, X.-H., Liu, J., Tu, G., Liu, Q., Tang, Y.-L., Jiang, Q., Xu, J.-H., et al. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115329 · Cited by 73 · see citing works
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Emerging tumor-on-chips with electrochemical biosensors
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PROTACs: A novel strategy for cancer drug discovery and development
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Recent Advances of Degradation Technologies Based on PROTAC Mechanism
Xiao, M., Zhao, J., Wang, Q., Liu, J., & Ma, L. (2022) · Biomolecules · doi:10.3390/biom12091257 · Cited by 66 · see citing works
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Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy
Peng, Y., Liu, J., Inuzuka, H., & Wei, W. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104572 · Cited by 66 · see citing works
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Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development
Tan, X., Huang, Z., Pei, H., Jia, Z., & Zheng, J. (2024) · iScience · doi:10.1016/j.isci.2024.110712 · Cited by 66 · see citing works
Deregulation of SPOP in Cancer
Zhang, H., Jin, X., & Huang, H. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-2801 · Cited by 65 · see citing works
Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy
Liu, J., Chen, T., Li, S., Liu, W., Wang, P., & Shang, G. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.06.004 · Cited by 63 · see citing works
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Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy
Zou, Z., Yang, L., Nie, H., Gao, J., Lei, S., Lai, Y., Zhang, F., Wagner, E., Yu, H., Chen, X., et al. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01266-z · Cited by 58 · see citing works
Long-Chain Acyl-CoA Synthetase 4–Mediated Fatty Acid Metabolism Sustains Androgen Receptor Pathway–Independent Prostate Cancer
Ma, Y., Zhang, X., Alsaidan, O. A., Yang, X., Sulejmani, E., Zha, J., Beharry, Z. M., Huang, H., Bartlett, M. G., Lewis, Z., et al. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0379 · Cited by 58 · see citing works
DNA framework-engineered chimeras platform enables selectively targeted protein degradation
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Targeting PGAM1 in cancer: An emerging therapeutic opportunity.
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Authors: Liu, J., Ma, J., Liu, Y., Xia, J., Li, Y., Wang, Z. P., & Wei, W.
Affiliations: Beth Israel Deaconess Medical Center (US)
Bengbu Medical College (CN)
Corresponding author: Wang, Z. Peter
Wei, Wenyi
ORCID: Liu, Jing
Ma, Jia
Liu, Yi
Xia, Jun
Li, Yuyun
Wang, Z. Peter
Wei, Wenyi
Venue: Seminars in Cancer Biology
Publisher: Elsevier BV
Published: 2020-12
Volume: 67
Issue: Pt 2
Pages: 171-179
ISSN: 1044-579X (ISSN-L)
DOI: 10.1016/j.semcancer.2020.02.006
OpenAlex: W3005962215
Cited by: 186
References: 120
Citations by year: 2026: 19 · 2025: 32 · 2024: 39 · 2023: 25 · 2022: 35 · 2021: 19 · 2020: 17
FWCI: 2.39
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Seminars in Cancer Biology (publishedVersion)
PubMed (publishedVersion)
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, E3 ubiquitin ligase, targeted protein degradation, MDM2, VHL, IAP, cereblon, cancer therapy, transcription factors, scaffold proteins, oncoprotein, BCR-ABL, EGFR, cyclin-dependent kinases, RTK
MeSH terms: Humans, Neoplasms, Photochemotherapy, Recombinant Proteins, Drug Resistance, Neoplasm, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries, Molecular Targeted Therapy, Proteolysis

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PROTACs: A novel strategy for cancer therapy

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