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.
Highlights
Antihormonal therapies that directly antagonize the function of the estrogen receptor alpha (ERa; such as tamoxifen) or therapies that block the production of its ligand, estrogen, are the mainstay therapy for ER-positive (ERþ) breast cancer [1,2,3,4]
The molecule is characterized by a fluoropropyl pyrrolidinyl side chain that is molecularly distinct from other Selective estrogen receptor degraders (SERD) molecules
We examined the transcriptional activity of SAR439859 on other nuclear hormone receptors (NR) including ERb, glucocorticoid receptor, androgen receptor, progesterone receptor, and mineralocorticoid receptor
Summary
Antihormonal therapies that directly antagonize the function of the estrogen receptor alpha (ERa; such as tamoxifen) or therapies that block the production of its ligand, estrogen (such as aromatase inhibitors), are the mainstay therapy for ER-positive (ERþ) breast cancer [1,2,3,4]. These treatments markedly reduce the risk of recurrence from early-stage disease and improve outcomes in patients with advanced disease, relapse frequently occurs after prolonged treatment [1, 4,5,6]. There is rationale, in addition to ERa antagonism, that degradation of the ERa protein could have an impact on the ERa biology and efficacy of therapies targeting ERa
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