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AZD9496: an Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1- Mutant Breast Tumors in Preclinical Models Hazel M

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AZD9496: an Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1- Mutant Breast Tumors in Preclinical Models Hazel M Published OnlineFirst March 28, 2016; DOI: 10.1158/0008-5472.CAN-15-2357 Cancer Therapeutics, Targets, and Chemical Biology Research AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1- Mutant Breast Tumors in Preclinical Models Hazel M. Weir1, Robert H. Bradbury1, Mandy Lawson1, Alfred A. Rabow1, David Buttar1, Rowena J. Callis2, Jon O. Curwen1, Camila de Almeida1, Peter Ballard1, Michael Hulse1, Craig S. Donald1, Lyman J.L. Feron1, Galith Karoutchi1, Philip MacFaul1, Thomas Moss1, Richard A. Norman2, Stuart E. Pearson1, Michael Tonge2,Gareth Davies1,Graeme E.Walker2, Zena Wilson1, Rachel Rowlinson1, Steve Powell1, Claire Sadler1, Graham Richmond1, Brendon Ladd3, Ermira Pazolli4, Anne Marie Mazzola3, Celina D'Cruz3, and Chris De Savi3 Abstract Fulvestrant is an estrogen receptor (ER) antagonist admin- Combining AZD9496 with PI3K pathway and CDK4/6 inhi- istered to breast cancer patients by monthly intramuscular bitors led to further growth-inhibitory effects compared with injection. Given its present limitations of dosing and route monotherapy alone. Tumor regressions were also seen in a of administration, a more flexible orally available compound long-term estrogen-deprived breast model, where significant has been sought to pursue the potential benefits of this drug downregulation of ERa protein was observed. AZD9496 in patients with advanced metastatic disease. Here we report bound and downregulated clinically relevant ESR1 mutants the identification and characterization of AZD9496, a nonste- in vitro andinhibitedtumorgrowthinanESR1-mutant roidal small-molecule inhibitor of ERa,whichisapotent patient-derived xenograft model that included a D538G and selective antagonist and downregulator of ERa in vitro and mutation. Collectively, the pharmacologic evidence showed in vivo in ER-positive models of breast cancer. Significant that AZD9496 is an oral, nonsteroidal, selective estrogen þ tumor growth inhibition was observed as low as 0.5 mg/kg receptor antagonist and downregulator in ER breast cells þ dose in the estrogen-dependent MCF-7 xenograft model, where that could provide meaningful benefittoER breast cancer this effect was accompanied by a dose-dependent decrease in patients. AZD9496 is currently being evaluated in a phase I PR protein levels, demonstrating potent antagonist activity. clinical trial. Cancer Res; 76(11); 1–12. Ó2016 AACR. Introduction tors have been implicated in driving resistance in cells, for exam- ple, receptor tyrosine kinases (HER2), EGFR, and their down- With over 70% of breast cancers expressing the estrogen recep- stream signaling pathways, Ras/Raf/MAPK and PI3K/protein tor alpha (ERa), treatment with antihormonal therapies that kinase B (AKT) signaling (3–5). In some instances, signaling from directly antagonize ER function (e.g., tamoxifen) or therapies different growth factor receptor kinases leads to phosphorylation that block the production of the ligand, estrogen (e.g., aromatase of various proteins in the ER pathway, including ER itself, leading inhibitors) are key to management of the disease both in adjuvant to ligand-independent activation of the ER pathway (6). and metastatic settings (1, 2). Despite initial efficacy seen with In the metastatic setting, 500 mg fulvestrant, given as 2 Â 250 endocrine therapies, the development of acquired resistance mg intramuscular injections, has been shown to offer additional ultimately limits the use of these agents although the majority benefit over the 250 mg dose with improved median overall of tumors continue to require ERa for growth. Through the use of survival (7, 8). Recent analysis of presurgical data from a number preclinical models and cell lines, changes in growth factor recep- of trials showed a dose-dependent effect on key biomarkers such as ER, progesterone receptor (PR), and Ki67 labeling index (9). Although fulvestrant is clearly effective in this later treatment 1Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, United Kingdom. 2Discovery Sciences, AstraZeneca, Alderley Park, Maccles- setting, there are still perceived limitations in its overall clinical field, United Kingdom. 3Oncology iMed, AstraZeneca R&D Boston, benefit due to very low bioavailability, the time taken to achieve 4 Gatehouse Drive, Waltham, Massachusetts. H3 Biomedicine, Cam- plasma steady-state of 3–6 months and ultimately the level of ERa bridge, Massachusetts. reduction seen in clinical samples (10, 11). It is widely believed Note: Supplementary data for this article are available at Cancer Research that a potent, orally bioavailable SERD that could achieve higher Online (http://cancerres.aacrjournals.org/). steady-state free drug levels more rapidly would have the potential Corresponding Author: Hazel M. Weir, AstraZeneca, Alderley Park, Macclesfield, for increased receptor knockdown and lead to quicker clinical Cheshire, SK10 4TG, United Kingdom. Phone: 016-2551-3799; Fax: 016-2551- responses, reducing the possibility of early relapses (12). More- 9173; E-mail: [email protected] over, the recent discovery of ESR1 mutations in metastatic breast doi: 10.1158/0008-5472.CAN-15-2357 cancer patients that had received prior endocrine treatments, Ó2016 American Association for Cancer Research. where the mutated receptor is active in the absence of estrogen, www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 28, 2016; DOI: 10.1158/0008-5472.CAN-15-2357 Weir et al. highlights an important potential resistance mechanism. Preclin- ERa structure as the search model (28). Quality checks on the ical in vitro and in vivo studies have shown a reduction in signaling protein structures were carried out using the validation tools in from ESR1 mutants by tamoxifen and fulvestrant, but at higher Coot (29). The final structure has been deposited in the Protein doses than required to inhibit the wild-type receptor, which Databank with the ID code given in Supplementary Table S1. implies that more potent SERDs may be required to treat these patients or to use in the adjuvant setting to limit the emergence of Stable isotope labeling of amino acids and mass spectrometry mutations (13–15). Stable isotope labeling of amino acids (SILAC) assays were Achieving oral bioavailability has remained a key challenge in carried out as described previously (30) and detailed in Supple- the design of ER downregulators and until now no oral estrogen mentary Methods. Compound-treated samples were analyzed by receptor downregulators, other than GDC-0810 and RAD1901, mass spectrometry using relative peptide quantification by select- have progressed into clinical trials, despite encouraging reports ed reaction monitoring (SRM). Degradation half-life was mea- from others of preclinical activity in mouse xenograft models sured using the one-phase exponential decay equation in Graph- À (16–21). Here, we describe a chemically novel, nonsteroidal ERa Pad PRISM (Y ¼ Span.e K.X þ Plateau), where X is time and Y is antagonist and downregulator, AZD9496, that can be adminis- response, which starts out as Span þ Plateau and decreases to tered orally and links increased tumor growth inhibition to Plateau with a rate constant K. enhanced biomarker modulation compared with fulvestrant in a preclinical in vivo model of breast cancer. Moreover, we show Rat uterine and xenograft studies that AZD9496 is a potent inhibitor of ESR1-mutant receptors and All studies involving animals in the United Kingdom were can drive tumor growth inhibition in a patient-derived ESR1 conducted in accordance with UK Home Office legislation, the mutant in vivo model (PDX). Hence, AZD9496 is anticipated to Animal Scientific Procedures Act 1986, and AstraZeneca Global yield improved bioavailability and clinical benefit through Bioethics policy or with US federal, state, and institutional guide- enhanced ER pathway modulation. lines in an Association for Assessment and Accreditation of Laboratory Animal Care–accredited facility. The rat uterine weight Materials and Methods assay for the measurement of estrogenic activity was performed as Cell lines and culture described previously (31). Details of individual models, protein All AZ cell lines were tested and authenticated by short-tandem analysis of tumor fragments, and pharmacokinetic analysis of repeat (STR) analysis. MCF-7 was obtained from DSMZ and last plasma samples are included in Supplementary Methods. STR tested in February 2013. MDA-MB-361 (STR tested in October 2011), MDA-MB-134 (STR tested in October 2010), T47D (STR Results tested in June 2012), CAMA-1 (STR tested in March 2012), AZD9496 is a selective ERa antagonist, downregulator, and þ HCC1428 (STR tested in December 2011), HCC70 (STR tested inhibitor of ER tumor cell growth in October 2013), LnCAP (STR tested in August 2011), MDA-MB- AZD9496 ((E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methyl- 468 (STR tested in March 2014), BT474 (STR tested in July 2013), propyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl) PC3 (STR tested in October 2012), HCT116 (STR tested in August phenyl)acrylic acid; Fig. 1A) was identified through structure-based 2011) were all obtained from the ATCC. HCC1428-LTED cell line design and iterative medicinal chemistry structure–activity relation- (STR tested in November 2012) was kindly provided by Carlos ship (SAR) studies from a novel ER-binding motif (32). A directed Arteaga (Vanderbilt University, Nashville, TN; ref. 22). Cells were
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