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Cited by 69Estrogen and related hormone effectsAdvanced Breast Cancer TherapiesBreast Cancer Treatment Studies

SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models

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Shomali, Maysoun, Cheng, Jane, Sun, Fangxian, Koundinya, Malvika, Guo, Zhuyan, Hebert, Andrew T., McManus, Jessica, Levit, Mikhail N. +22 more·2021·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-20-0390

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Abstract

Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

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  • Persistent ERα expression post-Tamoxifen therapy motivates SERD development, such as Fulvestrant, which improved clinical benefits after failure of other endocrine therapies.

    “It has been reported that persistent ERα expression post-Tamoxifen therapy motivates SERD development, such as Fulvestrant, which improved clinical benefits after failure of other endocrine therapies36.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [36]

    The Introduction says tamoxifen stabilizes ERα and gives ERα degradation as a rationale for SERDs. It also identifies fulvestrant as a SERD and reports clinical benefits after failure of other hormonal therapies. It does not establish that ERα expression persists specifically after tamoxifen therapy; the Discussion describes benefit for post-tamoxifen patients as a potential outcome for SAR439859, not a demonstrated finding about persistent expression. Page numbers were not available in our copy. (LLM, conf=0.83)

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Authors
Shomali, M., Cheng, J., Sun, F., Koundinya, M., Guo, Z., Hebert, A. T., McManus, J., Levit, M. N., Hoffmann, D., Courjaud, A., Arrebola, R., Cao, H., Pollard, J., Lee, J. S., Besret, L., Caron, A., Bangari, D. S., Abecassis, P.-Y., Schio, L., El-Ahmad, Y., Halley, F., Tabart, M., Certal, V., Thompson, F., McCort, G., Filoche-Rommé, B., Cheng, H., Garcia-Echeverria, C., Debussche, L., & Bouaboula, M.
Affiliations
  • 1Sanofi, Research and Development, Cambridge, Massachusetts
  • Sanofi (France) (FR)
  • 2Sanofi, Research and Development, Vitry-sur-Seine, France.
  • 3Sanofi, Research and Development, Waltham, Massachusetts.
Corresponding author
Shomali, Maysoun
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2021-02-01
Volume
20
Issue
2
Pages
250-262
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-20-0390
OpenAlex
W3112130448
Cited by
69
References
2
Citations by year
2026: 4 · 2025: 15 · 2024: 14 · 2023: 16 · 2022: 11 · 2021: 9
FWCI
5.42
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
selective estrogen receptor degrader, estrogen receptor-positive breast cancer, endocrine therapy resistance, tamoxifen resistance, oral bioavailability, fulvestrant, MCF-7 xenografts, anticancer activity
MeSH terms
Animals, Breast Neoplasms, Disease Models, Animal, Female, Humans, Receptors, Estrogen, Mice

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