Cited by 146Protein Degradation and InhibitorsProstate Cancer Treatment and ResearchUbiquitin and proteasome pathways

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First targeted protein degrader hits the clinic

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Mullard, Asher·2019·Nature Reviews Drug Discovery

DOI 10.1038/d41573-019-00043-6

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BackgroundInfluential
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Background
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“, 2019), which, in addition to PROteolysis-TArgeting chimeras (PROTACS) (Mullard, 2019), are paving the way to explore the Ub system in drug discovery development programs by modulating the turnover of key targets in the context of cancer, dementia, and inflammation (Pinto-Fernandez and Kessler, 2016; Harrigan et al.”
Background
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BackgroundInfluential
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Background
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Background
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Background
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“One of the AR degraders utilizing PROTAC technology is in a phase I clinical trial (51).”
Method
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“PROTACs have recently proven effective in the clinic with androgen and estrogen receptor targeting PROTACs for cancer (Mullard, 2019).”
Background
Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs
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Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands
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Exploiting E3 ubiquitin ligases to reeducate the tumor microenvironment for cancer therapy
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Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology
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“Proteolysis-targeting chimaeras (PROTACs), which are bispecific binders, have recently gained much attention, with the first one reaching clinical studies [112, 113].”
Background
Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer
Hung, C.-L., Liu, H.-H., Fu, C., Yeh, H.-H., Hu, T.-L., Kuo, Z., Lin, Y.-C., Jhang, M.-R., Hwang, C.-S., Hsu, H., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104500 · Cited by 40
“These compounds either by employing cere-blon (CRBN)- (ARV-110, TD-802, ARD-2128) or von Hippel-Lindau (VHL)- (ARCC4, ARD-266, ARD-69, ARD-61) mediated degradation, effectively inhibit tumor proliferation in both androgen-dependent as well as CRPC models.”
Regulation of large and small G proteins by ubiquitination
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“This novel technology has led to first ‘degrading’ drug that is targeted to the androgen receptor for prostate cancer treatment, and is now in phase 1 clinical trials [reviewed in (98,99)].”
Background
PROTAC: targeted drug strategy. Principles and limitations
Koroleva, O. A., Dutikova, Y. V., Trubnikov, A. V., Zenov, F. A., Manasova, E. V., Shtil, A. A., & Kurkin, A. V. (2022) · Russian Chemical Bulletin · doi:10.1007/s11172-022-3659-z · Cited by 38
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Photopharmacology of Proteolysis-Targeting Chimeras: A New Frontier for Drug Discovery
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“, 2020), and, in 2019, two oral PROTACs, ARV-471 (NCT04072952) and ARV-110 (NCT03888612), have advanced into clinical trials for the treatment of metastatic breast cancer and prostate cancer, respectively (Mullard, 2019; Wang Y. et al., 2020).”
Background
Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions
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“In 2019 and 2020, clinical trials of PROTACs were established for two cancer targets: estrogen (ER) and androgen (AR) receptors [141,142].”
Background
The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents
Coll-Martínez, B., Delgado, A., & Crosas, B. (2020) · Molecules · doi:10.3390/molecules25245956 · Cited by 28
A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective
Kwon, J. J., & Hahn, W. C. (2021) · Molecular and Cellular Biology · doi:10.1128/mcb.00627-20 · Cited by 26
Engineering Single Pan-Specific Ubiquibodies for Targeted Degradation of All Forms of Endogenous ERK Protein Kinase
Stephens, E. A., Ludwicki, M. B., Meksiriporn, B., Li, M., Ye, T., Monticello, C., Forsythe, K. J., Kummer, L., Zhou, P., Plückthun, A., et al. (2021) · ACS Synthetic Biology · doi:10.1021/acssynbio.1c00357 · Cited by 27
Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo
Wortmann, L., Lindenthal, B., Muhn, P., Walter, A., Nubbemeyer, R., Heldmann, D., Sobek, L., Morandi, F., Schrey, A. K., Moosmayer, D., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01382 · Cited by 23
Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity
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“Meanwhile, in 2019, for the first time, PROTAC degraders ARV-110 and ARV-471 entered phase 1 clinical trials for the treatment of prostate cancer and breast cancer, respectively [18].”
Background
Recent Progress in DNA Damage Response-Targeting PROTAC Degraders
Cheng, B., Fei, X., Ding, Z., Peng, X., Su, Z., Pan, W., & Chen, J. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00015 · Cited by 27
Targeted protein degradation in antibacterial drug discovery?
Gopal, P., & Dick, T. (2019) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2019.11.005 · Cited by 24
“…Lab in 2008, which could bind and induce degradation of the androgen receptor (AR) to the first PROTAC molecule (ARV-110) to enter the clinic with a Phase I trial for prostate cancer earlier this year, this field has rapidly grown and gained attention from the scientific community (Mullard, 2019).”
Background
Structure driven compound optimization in targeted protein degradation
Leissing, T. M., Luh, L. M., & Cromm, P. M. (2020) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2020.11.005 · Cited by 22
Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy
Yuan, M., Chu, Y., & Duan, Y. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.691093 · Cited by 27
“This drug design strategy has increasingly attracted attention, especially upon the first PROTAC entering clinical trials in 2019 (Mullard, 2019).”
Background
Electrophilic Natural Products as Drug Discovery Tools
Gehrtz, P., & London, N. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.03.008 · Cited by 25
Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation
Li, Y., Bao, K., Sun, J., Ge, R., Zhang, Q., Zhang, B., Yan, X., Li, J., Shi, F., Zhang, M., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01537-1 · Cited by 25
“Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule.”
Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src
Manda, S., Lee, N. K., Oh, D., & Lee, J. (2020) · Molecules · doi:10.3390/molecules25081948 · Cited by 22
Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective
Cui, Q., Huang, C., Liu, J., & Zhang, J. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01130 · Cited by 23
Targeted Protein Degradation: An Emerging Therapeutic Strategy in Cancer
Barghout, S. H. (2020) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520620666200410082652 · Cited by 21
Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor
Tsujimura, H., Naganuma, M., Ohoka, N., Inoué, T., Naito, M., Tsuji, G., & Demizu, Y. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00126 · Cited by 25
Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation
Wang, Y., Wei, T., Zhao, M., Huang, A., Sun, F., Chen, L., Lin, R., Xie, Y., Zhang, M., Xu, S., et al. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002550 · Cited by 24
Induced proximity at the cell surface
Till, N. A., Ramanathan, M., & Bertozzi, C. R. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02592-1 · Cited by 21
“PROTACs and molecular glues were the original launch point of the TPD field, and several such molecules are undergoing clinical evaluation 13,14 .”
Synthetic biology approaches for targeted protein degradation
Chen, R. P., Gaynor, A. S., & Chen, W. (2019) · Biotechnology Advances · doi:10.1016/j.biotechadv.2019.107446 · Cited by 18
“However, their ease of delivery makes them a powerful drug treatment option, and PROTACS have begun to enter clinical trials this year (Mullard, 2019).”
Background
Conformational Dynamics and Binding Kinetics Drive Mutant Selective Degradation of EGFR
Rosenberg, S., Shanahan, F., Yamazoe, S., Kschonsak, M., Zeng, Y. J., Lee, J., Plise, E. G., Yen, I., Rose, C. M., Quinn, J. G., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2023.01.007 · Cited by 18
Covalent Recruitment of NEDD4 for Targeted Protein Degradation: Rational Design of Small Molecular Degraders
He, X., Zeng, S., Wen, Y., Yang, T., Huang, C., Li, Y.-F., Zhang, Z., Ding, K., Liu, T., Tan, Y., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c18083 · Cited by 20
Proteostasis Dysregulation in Pancreatic Cancer
Arpalahti, L., Haglund, C., & Holmberg, C. I. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-38266-7_4 · Cited by 17
Molecular basis and dual ligand regulation of tetrameric estrogen receptor α/14-3-3ζ protein complex
Somsen, B. A., Sijbesma, E., Leysen, S., Honzejková, K., Visser, E. J., Cossar, P. J., Obšil, T., Brunsveld, L., & Ottmann, C. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104855 · Cited by 17
New Targets and Emergent Therapies for Osteoporosis
Brommage, R. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_329 · Cited by 18
Monovalent protein-degraders – Insights and future perspectives
Cornella‐Taracido, I., & Garcı́a-Echeverrı́a, C. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127202 · Cited by 19
Photoactive Bifunctional Degraders: Precision Tools To Regulate Protein Stability
Kounde, C. S., & Tate, E. W. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01542 · Cited by 17

Authors: Mullard, A.
Corresponding author: Mullard, Asher
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2019-03-06
Volume: 18
Issue: 4
Pages: 237-239
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/d41573-019-00043-6
OpenAlex: W2920736663
Cited by: 146
References: 0
Citations by year: 2026: 7 · 2025: 8 · 2024: 15 · 2023: 18 · 2022: 16 · 2021: 28 · 2020: 32 · 2019: 20
Type: other
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: targeted protein degradation, PROTACs, clinical trials, protein degraders, anticancer agents, E3 ubiquitin ligase, drug development

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