Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3<i>S</i>)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7<i>H</i>-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer

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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“…2A-D). These biological observations are in agreement with SAR439859 inducing conformational change in helix 12 of the ERa (53).…”

Section: Discussionsupporting

confidence: 88%

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

Shomali

Cheng

Sun

et al. 2021

Molecular Cancer Therapeutics

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“…This study mainly analyzes the clinical therapeutic effect of sequential therapy with tamoxifen (TAM) and letrozole (LTZ) versus LTZ monotherapy in the treatment of BC. It is shown that the tumor tissue of most BC patients is estrogen-dependent, and inhibiting estrogen stimulation of tumors can help to curb cancer progression [ 7 ]. Both TAM and LTZ are common antiestrogen drugs in clinic [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy, Safety, and Prognosis of Sequential Therapy with Tamoxifen and Letrozole versus Letrozole Monotherapy for Breast Carcinoma

Qian²

2022

Computational and Mathematical Methods in Medicine

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Objective. To explore the efficacy, safety, and patient prognosis of letrozole (LTZ) alone or in sequence with tamoxifen (TAM) for the treatment of breast carcinoma (BC). Methods. In this retrospective study, 150 patients with BC who received treatment in the First People’s Hospital of Ningyang County between January 2012 and January 2017 were selected. According to different treatment methods, 99 cases receiving sequential therapy with TAM and LTZ were included in the research group, and the remaining 51 patients receiving LTZ monotherapy were selected as the control group. The efficacy, safety, survival rate, recurrence rate, and blood lipid indices (total cholesterol, TC; triglyceride, TG; high-density lipoprotein cholesterol, HDL-C; and low-density lipoprotein cholesterol, LDL-C) of the two groups were observed and compared. Results. The overall response rate of the research group was statistically higher than that of the control group, and the incidence of adverse reactions was significantly lower. No evident difference was observed in 1-, 3-, or 5-year survival rates between the two groups, while the 3-5-year recurrence rate was obviously lower, and the improvement of blood lipid indices was significantly better in the research group compared with the control group. Conclusion. LTZ alone or in sequence with TAM is effective and safe for the treatment of BC, which can significantly improve the prognosis and blood lipid indices of BC patients.

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“…Amcenestrant antagonizes the binding of E2 to ER but also promotes the transition of ERα to an inactive conformation that leads to up to 98% receptor in in vitro assays. These dual properties lead to a deeper inhibition of ERα pathways and a more effective antiproliferative activity in ERα-dependent BC cell lines driven by mutant or wild-type ERα compared to other ERα inhibitors [82,83].…”

Section: Sar439859 (Amcenestrant)mentioning

confidence: 99%

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

Hernándo

Ortega-Morillo

Tapia

et al. 2021

IJMS

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Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.

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Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer

Cited by 62 publications

References 32 publications

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

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

Efficacy, Safety, and Prognosis of Sequential Therapy with Tamoxifen and Letrozole versus Letrozole Monotherapy for Breast Carcinoma

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

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