Cited by 534Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

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Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

Churcher, Ian·2018·Journal of Medicinal Chemistry

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Abstract

Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery; the many potential advantages and outstanding challenges which lie ahead of this technology are discussed.

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“As indicated in the examples summarized above, PROTACs offer an effective approach to address various Frontiers in Cell and Developmental Biology | www.frontiersin.org April 2022 | Volume 10 | Article 87272916 forms of emerging drug resistance in response to SMIs.”
BackgroundInfluential
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Background
Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin
Zhang, L., Li, L., Wang, X., Liu, H., Zhang, Y., Xie, T., Zhang, H., Li, X., Peng, T., Sun, X. H., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.09.008 · Cited by 125
Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update
Wu, T., Qin, Z., Tian, Y., Wang, J., Xu, C., Li, Z., & Bian, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00744 · Cited by 119
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 124
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 120
Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity
Zhang, X., Thummuri, D., Liu, X., Hu, W., Zhang, P., Khan, S., Yuan, Y., Zhou, D., & Zheng, G. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112186 · Cited by 123
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
Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands
Wang, Z., He, N., Guo, Z., Niu, C., Song, T., Guo, Y., Cao, K., Wang, A., Zhu, J., Zhang, X., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00919 · Cited by 120
Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations
Young, R. J., & Leeson, P. D. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00180 · Cited by 113
PDZ Domains as Drug Targets
Christensen, N. R., Čalyševa, J., Fernandes, E. F. A., Lüchow, S., Clemmensen, L. S., Haugaard‐Kedström, L. M., & Strømgaard, K. (2019) · Advanced Therapeutics · doi:10.1002/adtp.201800143 · Cited by 114
Targeted protein degrader development for cancer: advances, challenges, and opportunities
Fang, Y., Wang, S., Han, S., Zhao, Y., Yu, C., Liu, H., & Li, N. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.03.003 · Cited by 113
Small-Molecule Hydrophobic Tagging: A Promising Strategy of Druglike Technology for Targeted Protein Degradation
Xie, S., Zhu, J., Li, J., Zhan, F., Yao, H., Xu, J., & Xu, S. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00736 · Cited by 111
Delivering on the promise of protein degraders
O’Brien, M. N., Luthra, S. A., Brown, M. F., & Bartlett, D. W. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00652-2 · Cited by 109
PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies
Sincere, N. I., Anand, K., Ashique, S., Yang, J., & You, C. (2023) · Molecules · doi:10.3390/molecules28104014 · Cited by 112
“It is crucial to identify the guiding principles and provide reliable evaluation frameworks [67].”
Background
Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders
Shen, Y., Gao, G., Yu, X., Kim, H., Wang, L., Xie, L., Schwarz, M. C., Chen, X., Guccione, E., Liu, J., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01111 · Cited by 107
A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity
Yan, S., Yan, J., Liu, D., Li, X., Kang, Q., You, W., Zhang, J., Wang, L., Tian, Z., Lu, W., et al. (2021) · Theranostics · doi:10.7150/thno.59020 · Cited by 108
“While some progress has been achieved in developing cell-permeable and proteolytic-resistant peptide-based PROTACs via chemically-modified peptide sidechain and/or cell-penetrating peptide conjugation [11-14], none have entered into clinical trials or approval for clinical application [3, 15].”
Design and synthesis of selective degraders of EGFRL858R/T790M mutant
Zhang, X., Xu, F., Tong, L., Zhang, T., Xie, H., Lu, X., Ren, X., & Ding, K. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112199 · Cited by 110
Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)
Lu, Y., & Sun, H. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01248 · Cited by 104
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 107
Targeting EZH2 for cancer therapy: From current progress to novel strategies
Zeng, J., Zhang, J., Sun, Y. J., Wang, J., Ren, C., Banerjee, S., Ouyang, L., & Wang, Y. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114419 · Cited by 112
PROTAC-mediated crosstalk between E3 ligases
Steinebach, C., Kehm, H., Lindner, S., Vu, L. P., Köpff, S., Mármol, Á. L., Weiler, C., Wagner, K. G., Reichenzeller, M., Krönke, J., et al. (2019) · Chemical Communications · doi:10.1039/c8cc09541h · Cited by 101
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 104
Covalent Small Molecules as Enabling Platforms for Drug Discovery
Dalton, S. E., & Campos, S. (2019) · ChemBioChem · doi:10.1002/cbic.201900674 · Cited by 101
The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022
Pang, X., Xu, W., Liu, Y., Li, H., & Chen, L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115491 · Cited by 101
Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality
Kostić, M., & Jones, L. H. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.02.006 · Cited by 97
“This issue has recently been reviewed [44], [45], and we will not go into details here.”
Background
Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy
Lee, G. T., Nagaya, N., Desantis, J., Madura, K., Sabaawy, H. E., Kim, W.-J., Vaz, R. J., Cruciani, G., & Kim, I. Y. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0417 · Cited by 96
Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13
Yang, J., Chang, Y., Tien, J. C.-Y., Wang, Z., Zhou, Y., Zhang, P., Huang, W., Vo, J. N., Apel, I. J., Wang, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00384 · Cited by 99
Revisiting signal transducer and activator of transcription 3 (STAT3) as an anticancer target and its inhibitor discovery: Where are we and where should we go?
Huang, Q., Zhong, Y., Dong, H., Zheng, Q., Shi, S., Zhu, K., Qu, X., Hu, W., Zhang, X., & Wang, Y. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111922 · Cited by 94
Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands
Zhao, H., Wang, H., Mao, Y.-Z., Zhang, H., Xin, M., Xi, X.-X., Lei, H., Mao, S., Li, D., & Zhang, S. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01827 · Cited by 95
Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)
Cao, F., de Weerd, S., Chen, D., Zwinderman, M. R. H., van der Wouden, P. E., & Dekker, F. J. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112800 · Cited by 96
Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
Han, X., & Sun, Y. (2022) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2022.101062 · Cited by 89
Degrader–Antibody Conjugates: Emerging New Modality
Hong, K. B., & An, H. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01791 · Cited by 93

Authors: Churcher, I.
Affiliations: BenevolentBio, 40 Churchway, London NW1 1LW, U.K.
Corresponding author: Churcher, Ian
ORCID: Churcher, Ian
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2017-12-19
Volume: 61
Issue: 2
Pages: 444-452
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.7b01272
OpenAlex: W2769590617
Cited by: 491
References: 67
Citations by year: 2026: 45 · 2025: 61 · 2024: 49 · 2023: 56 · 2022: 53 · 2021: 54 · 2020: 84 · 2019: 64 · 2018: 22 · 2017: 1
FWCI: 4.43
Type: journal article
Language: en
Open access: closed
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: targeted protein degradation, PROTACs, bifunctional small molecules, protein degradation, drug discovery
MeSH terms: Humans, Peptides, Recombinant Proteins, Drug Design, Ubiquitin-Protein Ligases, Small Molecule Libraries, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Proteolysis

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Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

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