Abstract 44: The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer
Abstract
ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 44.
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ARV-471 showed evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.
“The interim data for ARV-471 revealed a manageable tolerability profile with robust signals of clinical efficacy41, a 42% clinical benefit rate in a heavily pretreated population and evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [41]
Interim data for ARV-471 revealed robust signals of clinical efficacy, with a 42% clinical benefit rate in a heavily pretreated population.
“The interim data for ARV-471 revealed a manageable tolerability profile with robust signals of clinical efficacy41, a 42% clinical benefit rate in a heavily pretreated population and evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [41]
Interim data for ARV-471 revealed a manageable tolerability profile.
“The interim data for ARV-471 revealed a manageable tolerability profile with robust signals of clinical efficacy41, a 42% clinical benefit rate in a heavily pretreated population and evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [41]
ARV-110 and ARV-471 use CRBN as the E3 ligase recruited to AR and ER to catalyse their ubiquitylation and proteasomal degradation.
“Recently, it was disclosed that both ARV-110 and ARV-471 use CRBN as the E3 ligase that is recruited to their respective targets, AR and ER, to catalyse their ubiquitylation and proteasomal degradation41,71.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [41]
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Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications
Knoll, N., Neamati, N., & Üren, A. (2026) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.5c00730 · Cited by 4 · see citing works
Implications of ubiquitination and the maintenance of replication fork stability in cancer therapy
Xia, D., Zhu, X., Wang, Y., Gong, P., Su, H.-S., & Xu, X. (2023) · Bioscience Reports · doi:10.1042/bsr20222591 · Cited by 3 · see citing works
“Moreover, oral PROTACs (ARV-110 and ARV-471) have entered clinical trial of prostate and breast cancer treatment [197,198].”
BackgroundAdvances and challenges of estrogen receptor-targeted agents in breast cancer
Hu, J., Zhong, S., Sun, H., Liu, J., & Fang, W. (2025) · Archives of Pharmacal Research · doi:10.1007/s12272-025-01583-9 · Cited by 2 · see citing works
“In preclinical models, vepdegestrant demonstrated superior efficacy over fulvestrant independent of ESR1 mutations, and no ER agonistic activity (Snyder et al. 2021; Qin et al. 2022).”
Kumar, H., & Sobhia, M. E. (2026) · Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5c07053 · Cited by 4 · see citing works
Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation
Yim, J., Lee, J., Kim, S., Choi, J., Yoon, S., Cho, H., Jung, S., Yoo, G., Lee, S., Park, H., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-73252-4 · Cited by 4 · see citing works
Nguyen, K. T., Nguyen, H. H., Phùng, H. T. T., Chung, K. L., & Vu, T. Y. (2024) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2024.2308778 · Cited by 2 · see citing works
Su, Z., Yin, S., & Wu, Y. (2024) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.4c06497 · Cited by 2 · see citing works
Targeting Oestrogen Receptor Signalling in Breast Cancer Therapy
Howell, S. J., & Howell, A. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-70875-6_22 · Cited by 2 · see citing works
The Latest Advancements of the PROTACs Based on CRBN E3 Ligase for Cancer Treatment
Stadnichenko, V. O., Borysko, P., & Tolstanova, G. M. (2025) · Current Pharmacology Reports · doi:10.1007/s40495-025-00409-y · Cited by 2 · see citing works
Targeted Protein Degraders- The Druggability Perspective
Singh, S., & Srivastava, P. (2023) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2023.10.023 · Cited by 1 · see citing works
Exploring the Role of PROTACs for the Treatment of Breast Cancer
Pannu, A. S., Goyal, R. K., & Goswami, S. (2024) · Springer eBooks · doi:10.1007/978-981-97-5077-1_12 · Cited by 1 · see citing works
Bao, X., Yin, X., Xǔ, J., Zhu, Z., Lu, W., Cai, Y., Dai, R., Zheng, Z., Xu, W., Mei, S., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118199 · Cited by 2 · see citing works
Furuhata, T., Yoshida, K., 凌嘉, 藤., Miyamoto, J., Moriyama, C., Masuda-Ozawa, T., Tsuchiya, H., Saeki, Y., & Okamoto, A. (2026) · Communications Chemistry · doi:10.1038/s42004-026-01895-x · Cited by 1 · see citing works
Contemporary Developments in PROTACs for Cancer Management: An In-Depth Review
Rahaman, S. A., Venkateswarlu, G., Patel, S., Mishra, P. S., Kumar, R., & Parvez, N. (2026) · Current Topics in Medicinal Chemistry · doi:10.2174/0115680266384226251013054011 · Cited by 1 · see citing works
A destination-driven framework for nanoparticle-enabled targeted protein degradation
Wang, Y., Xia, X., Xie, S., Tong, F., Liu, W., & Gao, H. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.05.009 · Cited by 1 · see citing works
“In 2019, the PROTAC molecules ARV-471, targeting the ER, and ARV-110, targeting the AR, advanced into clinical trials, marking a significant milestone in the transition of PROTAC technology from laboratory research to clinical application 55,56 .”
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Update Mammakarzinom 2021 Teil 5 – fortgeschrittenes Mammakarzinom
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“[15] Snyder LB, Flanagan JJ, Qian Y et al.”
InfluentialWITHDRAWN: Targeted protein degradation: A promising approach for cancer treatment
Khan, M. Z. I., Nazli, A., Naz, I., Khan, D., Haq, I., & Chen, J. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.09.004 · Cited by 1 · see citing works
RetractedIdegenerering i IT-bedrifter - åpenhet og nettverks betydning for idégenerering
Liafjell, T. A. (2014) · NORA - Norwegian Open Research Archives
Update Mammakarzinom 2021 Teil 4 – Prävention und frühe Krankheitsstadien
Thomssen, C., Fehm, T. N., Stickeler, E., Fasching, P. A., Janni, W., Kolberg‐Liedtke, C., Kolberg, H., Lüftner, D., Müller, V., Schütz, F., et al. (2022) · Senologie - Zeitschrift für Mammadiagnostik und -therapie · doi:10.1055/a-1816-1625
Destruction with a Purpose: Targeted Protein Degradation in Drug Discovery
Martinelli, P., Kofink, C. C., Boeck, G., Weinstabl, H., & Koegl, M. (2022) · Wiley eBooks · doi:10.1002/9783527836208.ch11
Taming the Beast: How to Optimize DMPK–PD Properties of Oral Degraders
Rynn, C., Vyver, A. J. V. D., Walz, A., Cantrill, C., & Wittwer, M. (2022) · doi:10.1002/9783527836208.ch12
Targeted Protein Degradation – The Story So Far
O’Donovan, D. H., Luh, L. M., & Cromm, P. M. (2022) · doi:10.1002/9783527836208.ch1 · Cited by 1 · see citing works
Update Mammakarzinom 2023 Teil 2 – Brustkrebs in fortgeschrittenen Krankheitsstadien
Lux, M. P., Hartkopf, A. D., Fehm, T. N., et al. (2023) · Senologie - Zeitschrift für Mammadiagnostik und -therapie · doi:10.1055/a-2183-3490
NEW CHEMICAL ENTITIES ENTERING PHASE III TRIALS IN 2023
Lin, D. W., Armstrong, M., Jiang, J. B., del Pozo, J., & Teijaro, C. N. (2024) · Medicinal chemistry reviews · doi:10.1021/mc-2024-vol59.ch18
- Authors
- Snyder, L. B., Flanagan, J. J., Qian, Y., Gough, S. M., Andreoli, M., Bookbinder, M., Cadelina, G., Bradley, J., Rousseau, E., Chandler, J., Willard, R., Pizzano, J., Crews, C. M., Crew, A. P., Houston, J., Moore, M. D., Peck, R., & Taylor, I.
- Affiliations
- Arvinas (United States) (US)
- Yale University (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2021-07-01
- Volume
- 81
- Issue
- 13_Supplement
- Pages
- 44-44
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W3180062435
- Cited by
- 126
- References
- 0
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 30 · 2023: 23 · 2022: 20 · 2021: 4 · 2014: 1
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- ARV-471, PROTACs, estrogen receptor alpha, E3 ubiquitin ligase, breast cancer, estrogen receptor-positive breast cancer, ESR1 mutations, oral bioavailability, MCF-7 xenografts, patient-derived xenografts
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