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SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD)

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SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD) Published OnlineFirst December 11, 2020; DOI: 10.1158/1535-7163.MCT-20-0390 MOLECULAR CANCER THERAPEUTICS | SMALL MOLECULE THERAPEUTICS SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models A C Maysoun Shomali1, Jane Cheng1, Fangxian Sun1, Malvika Koundinya1, Zhuyan Guo1, Andrew T. Hebert1, Jessica McManus1, Mikhail N. Levit1, Dietmar Hoffmann1, Albane Courjaud2, Rosalia Arrebola2, Hui Cao1, Jack Pollard1, Joon Sang Lee1, Laurent Besret2, Anne Caron2, Dinesh S. Bangari3, Pierre-Yves Abecassis2, Laurent Schio2, Youssef El-Ahmad2, Frank Halley2, Michel Tabart2, Victor Certal2, Fabienne Thompson2, Gary McCort2, Bruno Filoche-Romme2, Hong Cheng1, Carlos Garcia-Echeverria2, Laurent Debussche2, and Monsif Bouaboula1 ABSTRACT ◥ Primary treatment for estrogen receptor-positive (ERþ) both wild-type and mutant Y537S ER. Driven by its fluoropro- breast cancer is endocrine therapy. However, substantial evi- pyl pyrrolidinyl side chain, SAR439859 has demonstrated dence indicates a continued role for ER signaling in tumor broader and superior ER antagonist and degrader activities progression. Selective estrogen receptor degraders (SERD), such across a large panel of ERþ cells, compared with other SERDs as fulvestrant, induce effective ER signaling inhibition, although characterized by a cinnamic acid side chain, including improved clinical studies with fulvestrant report insufficient blockade of inhibition of ER signaling and tumor cell growth. Similarly, ER signaling, possibly due to suboptimal pharmaceutical prop- in vivo treatment with SAR439859 demonstrated significant erties. Furthermore, activating mutations in the ER have tumorregressioninERþ breast cancer models, including emerged as a resistance mechanism to current endocrine ther- MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and apies. New oral SERDs with improved drug properties are under HCI013, a patient-derived tamoxifen-resistant xenograft tumor. clinical investigation, but the biological profile that could trans- These findings indicate that SAR439859 may provide therapeu- late to improved therapeutic benefit remains unclear. Here, we tic benefit to patients with ERþ breast cancer, including those describe the discovery of SAR439859, a novel, orally bioavailable whohaveresistancetoendocrine therapy with both wild-type SERD with potent antagonist and degradation activities against and mutant ER. Introduction stitutive activity of the ERa, induction of tumor growth, reduced potency to anti-ERa therapies, and complete resistance to aromatase Antihormonal therapies that directly antagonize the function of the inhibitors (7–10). estrogen receptor alpha (ERa; such as tamoxifen) or therapies that Some ligands that target the ERa can increase levels of the ERa block the production of its ligand, estrogen (such as aromatase protein steady state due to biological feedback mechanisms such as inhibitors), are the mainstay therapy for ER-positive (ERþ) breast increases in the transcriptional compensation or thermodynamic cancer (1–4). Although these treatments markedly reduce the risk of stability upon ligand binding (11). For example, tamoxifen induces recurrence from early-stage disease and improve outcomes in patients stabilization of the ERa protein, which adopts a conformation with advanced disease, relapse frequently occurs after prolonged that may lead to agonist signaling (12–16). It has also been treatment (1, 4–6). Recently, recurrent mutations have been identified suggested that some mutations in the ERa, such as those affecting in the ligand-binding domain of ERa in approximately 25% to 40% of the Y537S or D538G amino acids, may be involved in stabilization patients who have relapsed after receiving one or more prior hormonal of the ERa (10, 16–19). Moreover, an increase in ERa stability could therapies (7–10). These mutations confer estrogen-independent, con- also result in ERa signaling leakage when continuous treatment coverage is not achieved. Altogether, there is rationale, in addition to ERa antagonism, that degradation of the ERa protein could 1Sanofi, Research and Development, Cambridge, Massachusetts 2Sanofi, a fi Research and Development, Vitry-sur-Seine, France. 3Sanofi, Research and have an impact on the ER biology and ef cacy of therapies Development, Waltham, Massachusetts. targeting ERa. Selective estrogen receptor degraders (SERD), such as fulvestrant, Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). bind to the ERa to induce a conformational change that not only antagonizes ERa function, but also causes its proteasome-mediated Corresponding Author: Maysoun Shomali, Sanofi (United States), 640 Memorial degradation to more effectively inhibit ERa signaling. Fulvestrant is an Drive, Cambridge, MA 02478. Phone: 617-665-4945; E-mail: þ maysoun.shomali@sanofi.com approved SERD indicated for the treatment of ER metastatic breast cancer in postmenopausal women with disease progression following Mol Cancer Ther 2021;20:250–62 anti-estrogen therapy (20). Fulvestrant has demonstrated preclinical doi: 10.1158/1535-7163.MCT-20-0390 and clinical benefits after failure of other hormonal therapies (21–23). Ó2020 American Association for Cancer Research. However, fulvestrant, a steroid with a neutral and lipophilic side AACRJournals.org | 250 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst December 11, 2020; DOI: 10.1158/1535-7163.MCT-20-0390 SAR439859 Is a Novel SERD with Improved Antitumor Activity chain, requires unconventional long-acting intramuscular depot Compounds formulation, limiting its dose and exposure for maximal receptor SAR439859 was synthesized as described in WO2017140669, engagement (24, 25). as Example 51 (38). GDC0810 and AZD9496 were synthesized To address the preceding pharmacologic shortcomings posed as described in WO2012037410 (Example 111; ref. 39) and by fulvestrant, several novel SERDs have entered clinical trials includ- WO2014191726 (Example 1; ref. 40), respectively. Both AZD-SAR ing GDC-0810 (NCT 01823835), AZD9496 (NCT02248090), and GDC-SAR were made as described in WO2018091153 (Example AZD9833 (NCT03616586), GDC-0927 (NCT02316509), and GDC- 255 and 256, respectively; ref. 41). 9545 (NCT03916744, NCT03332797; refs. 26–28). These novel SERDs, which are chemically distinct from fulvestrant, can be classified In-cell Western assay into two major groups based on the chemical structure of their side MCF7 cells were seeded at a density of 15,000 cells per well into flat chain that is key in driving ERa degradation (29–31). GDC-0927 clear bottom tissue cultured-treated 384-well plates (Corning) in is characterized by a fluoroalkylamine side chain, whereas GDC-0810, IMEM with 5% CSS FBS. After treatment with ligand at the indicated AZD9496, and LSZ102 each have a cinnamic acid side chain concentrations, plates were washed, fixed 10% with neutral buffered (26, 27, 29, 32–34). It is not well understood whether the different formalin, permeabilized with PBS containing 0.1% Triton X-100, and side chains and/or their abilities to induce ERa degradation trans- blocked with Odyssey Blocking Buffer (LI-COR). The fixed cells were late to differences in their biology and antitumor activities. More- incubated with rabbit anti-ERa antibody (SP-1; MA5-14501; Thermo over, these SERDs have presented conflicting data in their relative Fisher Scientific), washed and stained with Alexa Fluor 488 goat anti- abilities to induce ERa agonist activity or promote complete ERa rabbit secondary antibody (Invitrogen) and Hoechst DNA stain to degradation (26, 28, 35). determine cell number. ERa levels were quantitated using the acumen To better define the molecular features to achieve optimal clinical eX3 imaging system. Percent residual ERa was defined as normalized activity of SERDs, it is crucial to understand the relationship between ERa treated cells/normalized ERa untreated cells Â100. the molecular structure of the drug, level of ERa degradation, and the subsequent impact on antitumor activity. Here, we describe Simple Western assay SAR439859, a novel, nonsteroidal, orally bioavailable SERD that bears Cells and tissues were lysed with an RIPA buffer (Boston BioPro- a fluoropropyl pyrrolidinyl side chain and, unlike SERDs with a ducts) or with tissue protein extraction reagent with Halt protease cinnamic acid side chain, SAR439859 has demonstrated strong inhibitors and EDTA (Thermo Fisher Scientific), respectively. Proteins ERa antagonist activity and potently induces its degradation, which from cell or tissue lysates were separated by capillary electrophoresis results in improved efficacy of both in vitro and in vivo ERþ breast using the Simple Western assay (ProteinSimple), as described previ- cancer models. ously (29) and probed with rabbit anti-ERa antibody (Cell Signaling Technologies, 13258) and b-actin (Cell Signaling Technologies, 3700). ERa levels were quantitated using the Compass software (Protein- Materials and Methods Simple); percent ERa was calculated by normalizing ERa values to Key details of the materials and methods used in this study are b-actin and then expressed as a percentage of the normalized value of provided below (see Supplementary Appendix for additional infor- the untreated cells. mation). Animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory
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