Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

Fanning, S. W.; Hodges-Gallagher, L.; Myles, D. C.; Sun, R.; Fowler, C. E.; Plant, I. N.; Green, B. D.; Harmon, C. L.; Greene, G. L.; Kushner, P. J.

doi:10.1038/s41467-018-04413-3

Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

Journal Article · Mon Jun 18 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-04413-3· OSTI ID:1511719

Fanning, S. W. ^[1]; Hodges-Gallagher, L. ^[2]; Myles, D. C. ^[2]; Sun, R. ^[2]; Fowler, C. E. ^[1]; Plant, I. N. ^[3]; Green, B. D. ^[1]; Harmon, C. L. ^[2]; ^[1]; Kushner, P. J. ^[2]

Univ. of Chicago, IL (United States)
Olema Pharmaceuticals, San Francisco, CA (United States)
Harvard Medical School, Boston, MA (United States)

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); Susan G. Komen Foundation; Virginia and D.K. Ludwig Fund for Cancer Research

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1511719

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (42)

Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies: Biological effects of fulvestrant in breast cancer Agrawal, Amit; Robertson, John F. R.; Cheung, Kwok L. International Journal of Cancer, Vol. 138, Issue 1 https://doi.org/10.1002/ijc.29682	journal	July 2015
Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. Berry, M.; Metzger, D.; Chambon, P. The EMBO Journal, Vol. 9, Issue 9 https://doi.org/10.1002/j.1460-2075.1990.tb07469.x	journal	September 1990
Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu Benz, Christopher C.; Scott, Gary K.; Sarup, Jay C. Breast Cancer Research and Treatment, Vol. 24, Issue 2 https://doi.org/10.1007/BF01961241	journal	June 1992
Bidirectional cross talk between ERα and EGFR signalling pathways regulates tamoxifen-resistant growth Britton, D. J.; Hutcheson, I. R.; Knowlden, J. M. Breast Cancer Research and Treatment, Vol. 96, Issue 2 https://doi.org/10.1007/s10549-005-9070-2	journal	October 2005
The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen Shiau, Andrew K.; Barstad, Danielle; Loria, Paula M. Cell, Vol. 95, Issue 7 https://doi.org/10.1016/S0092-8674(00)81717-1	journal	December 1998
Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial Robertson, John F. R.; Bondarenko, Igor M.; Trishkina, Ekaterina The Lancet, Vol. 388, Issue 10063 https://doi.org/10.1016/S0140-6736(16)32389-3	journal	December 2016
Structural Insights into the Mode of Action of a Pure Antiestrogen Pike, Ashley C. W.; Brzozowski, A. Marek; Walton, Julia Structure, Vol. 9, Issue 2 https://doi.org/10.1016/S0969-2126(01)00568-8	journal	February 2001
The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy Wardell, Suzanne E.; Marks, Jeffrey R.; McDonnell, Donald P. Biochemical Pharmacology, Vol. 82, Issue 2 https://doi.org/10.1016/j.bcp.2011.03.031	journal	July 2011
Effects of fulvestrant 750mg in premenopausal women with oestrogen-receptor-positive primary breast cancer Young, O. E.; Renshaw, L.; Macaskill, E. J. European Journal of Cancer, Vol. 44, Issue 3 https://doi.org/10.1016/j.ejca.2007.11.007	journal	February 2008
Agonist-like SERM effects on ERα-mediated repression of MMP1 promoter activity predict in vivo effects on bone and uterus Scafonas, Angela; Reszka, Alfred A.; Kimmel, Donald B. The Journal of Steroid Biochemistry and Molecular Biology, Vol. 110, Issue 3-5 https://doi.org/10.1016/j.jsbmb.2007.10.013	journal	June 2008
Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance Lewis, Joan S.; Jordan, V. Craig Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 591, Issue 1-2 https://doi.org/10.1016/j.mrfmmm.2005.02.028	journal	December 2005
DNA profiling analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination Korch, Christopher; Spillman, Monique A.; Jackson, Twila A. Gynecologic Oncology, Vol. 127, Issue 1 https://doi.org/10.1016/j.ygyno.2012.06.017	journal	October 2012
Optimization of a Novel Binding Motif to ( E )-3-(3,5-Difluoro-4-((1 R ,3 R )-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b ]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist De Savi, Chris; Bradbury, Robert H.; Rabow, Alfred A. Journal of Medicinal Chemistry, Vol. 58, Issue 20 https://doi.org/10.1021/acs.jmedchem.5b00984	journal	October 2015
Molecular basis of agonism and antagonism in the oestrogen receptor Brzozowski, Andrzej M.; Pike, Ashley C. W.; Dauter, Zbigniew Nature, Vol. 389, Issue 6652 https://doi.org/10.1038/39645	journal	October 1997
Full antagonism of the estrogen receptor without a prototypical ligand side chain Srinivasan, Sathish; Nwachukwu, Jerome C.; Bruno, Nelson E. Nature Chemical Biology, Vol. 13, Issue 1 https://doi.org/10.1038/nchembio.2236	journal	November 2016
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer Toy, Weiyi; Shen, Yang; Won, Helen Nature Genetics, Vol. 45, Issue 12 https://doi.org/10.1038/ng.2822	journal	November 2013
The Human Estrogen Receptor-α Is a Ubiquitinated Protein Whose Stability Is Affected Differentially by Agonists, Antagonists, and Selective Estrogen Receptor Modulators Wijayaratne, Ashini L.; McDonnell, Donald P. Journal of Biological Chemistry, Vol. 276, Issue 38 https://doi.org/10.1074/jbc.M101097200	journal	July 2001
Interaction of Transcriptional Intermediary Factor 2 Nuclear Receptor Box Peptides with the Coactivator Binding Site of Estrogen Receptor α Wärnmark, Anette; Treuter, Eckardt; Gustafsson, Jan-Åke Journal of Biological Chemistry, Vol. 277, Issue 24 https://doi.org/10.1074/jbc.M200764200	journal	April 2002
Differential SERM Effects on Corepressor Binding Dictate ERα Activity in Vivo Webb, Paul; Nguyen, Phuong; Kushner, Peter J. Journal of Biological Chemistry, Vol. 278, Issue 9 https://doi.org/10.1074/jbc.M208501200	journal	December 2002
Synthesis and structure–activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution Gauthier, Sylvain; Cloutier, Julie; Dory, Yves L. Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 20, Issue 2 https://doi.org/10.1080/14756360500043448	journal	April 2005
Oxidative Stress and AP-1 Activity in Tamoxifen-Resistant Breast Tumors In Vivo Schiff, R. Journal of the National Cancer Institute, Vol. 92, Issue 23 https://doi.org/10.1093/jnci/92.23.1926	journal	December 2000
RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models Garner, Fiona; Shomali, Maysoun; Paquin, Dotty Anti-Cancer Drugs, Vol. 26, Issue 9 https://doi.org/10.1097/CAD.0000000000000271	journal	January 2015
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes Minor, Wladek; Cymborowski, Marcin; Otwinowski, Zbyszek Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8 https://doi.org/10.1107/S0907444906019949	journal	July 2006
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase Kato, S.; Endoh, H.; Masuhiro, Y. Science, Vol. 270, Issue 5241 https://doi.org/10.1126/science.270.5241.1491	journal	December 1995
Structure Fluctuations and Conformational Changes in Protein Binding Ruvinsky, Anatoly M.; Kirys, Tatsiana; Tuzikov, Alexander V. Journal of Bioinformatics and Computational Biology, Vol. 10, Issue 02 https://doi.org/10.1142/S0219720012410028	journal	April 2012
Mechanisms of Tumor Regression and Resistance to Estrogen Deprivation and Fulvestrant in a Model of Estrogen Receptor–Positive, HER-2/ neu -Positive Breast Cancer Massarweh, Suleiman; Osborne, C. Kent; Jiang, Shou Cancer Research, Vol. 66, Issue 16 https://doi.org/10.1158/0008-5472.CAN-05-4045	journal	August 2006
Tamoxifen Resistance in Breast Tumors Is Driven by Growth Factor Receptor Signaling with Repression of Classic Estrogen Receptor Genomic Function Massarweh, S.; Osborne, C. K.; Creighton, C. J. Cancer Research, Vol. 68, Issue 3 https://doi.org/10.1158/0008-5472.CAN-07-2707	journal	February 2008
Development of Resistance to Targeted Therapies Transforms the Clinically Associated Molecular Profile Subtype of Breast Tumor Xenografts Creighton, C. J.; Massarweh, S.; Huang, S. Cancer Research, Vol. 68, Issue 18 https://doi.org/10.1158/0008-5472.CAN-08-1404	journal	September 2008
Emergence of Constitutively Active Estrogen Receptor- Mutations in Pretreated Advanced Estrogen Receptor-Positive Breast Cancer Jeselsohn, R.; Yelensky, R.; Buchwalter, G. Clinical Cancer Research, Vol. 20, Issue 7 https://doi.org/10.1158/1078-0432.CCR-13-2332	journal	January 2014
Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance Malorni, L.; Giuliano, M.; Migliaccio, I. Molecular Cancer Research, Vol. 14, Issue 5 https://doi.org/10.1158/1541-7786.MCR-15-0423	journal	March 2016
Measuring Residual Estrogen Receptor Availability during Fulvestrant Therapy in Patients with Metastatic Breast Cancer van Kruchten, Michel; de Vries, Elisabeth G.; Glaudemans, Andor W. Cancer Discovery, Vol. 5, Issue 1 https://doi.org/10.1158/2159-8290.CD-14-0697	journal	November 2014
Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer Zhou, Yamei; Yau, Christina; Gray, Joe W. BMC Cancer, Vol. 7, Issue 1 https://doi.org/10.1186/1471-2407-7-59	journal	April 2007
First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer Goetz, Matthew P.; Suman, Vera J.; Reid, Joel M. Journal of Clinical Oncology, Vol. 35, Issue 30 https://doi.org/10.1200/JCO.2017.73.3246	journal	October 2017
Elevated Levels of Epidermal Growth Factor Receptor/c-erbB2 Heterodimers Mediate an Autocrine Growth Regulatory Pathway in Tamoxifen-Resistant MCF-7 Cells Knowlden, Janice M.; Hutcheson, Iain R.; Jones, Helen E. Endocrinology, Vol. 144, Issue 3 https://doi.org/10.1210/en.2002-220620	journal	March 2003
A New Selective Estrogen Receptor Modulator with Potent Uterine Antagonist Activity, Agonist Activity in Bone, and Minimal Ovarian Stimulation Geiser, Andrew G.; Hummel, Conrad W.; Draper, Michael W. Endocrinology, Vol. 146, Issue 10 https://doi.org/10.1210/en.2005-0024	journal	October 2005
The estrogen antagonist ICI 182,780 reduces cancellous bone volume in female rats. Gallagher, A.; Chambers, T. J.; Tobias, J. H. Endocrinology, Vol. 133, Issue 6 https://doi.org/10.1210/endo.133.6.8243306	journal	December 1993
Coactivator Proteins as Determinants of Estrogen Receptor Structure and Function: Spectroscopic Evidence for a Novel Coactivator-Stabilized Receptor Conformation Tamrazi, Anobel; Carlson, Kathryn E.; Rodriguez, Alice L. Molecular Endocrinology, Vol. 19, Issue 6 https://doi.org/10.1210/me.2004-0458	journal	June 2005
Metformin reduces glycometabolism of papillary thyroid carcinoma in vitro and in vivo Shen, Chen-Tian; Wei, Wei-Jun; Qiu, Zhong-Ling Journal of Molecular Endocrinology, Vol. 58, Issue 1 https://doi.org/10.1530/JME-16-0134	journal	January 2017
Mechanisms of tamoxifen resistance Ring, Alistair; Dowsett, Mitch Endocrine-Related Cancer https://doi.org/10.1677/erc.1.00776	journal	December 2004
Pure oestrogen antagonists for the treatment of advanced breast cancer Howell, Anthony Endocrine-Related Cancer https://doi.org/10.1677/erc.1.00846	journal	September 2006
Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation Fanning, Sean W.; Mayne, Christopher G.; Dharmarajan, Venkatasubramanian eLife, Vol. 5 https://doi.org/10.7554/eLife.12792	journal	February 2016

Cited By (4)

Discovery of novel natural compound inhibitors targeting estrogen receptor α by an integrated virtual screening strategy Yu, Enguang; Xu, Yueping; Shi, Yanbo Journal of Molecular Modeling, Vol. 25, Issue 9 https://doi.org/10.1007/s00894-019-4156-7	journal	August 2019
Emerging modes-of-action in drug discovery Valeur, Eric; Narjes, Frank; Ottmann, Christian MedChemComm, Vol. 10, Issue 9 https://doi.org/10.1039/c9md00263d	journal	January 2019
Next-Generation ERα Inhibitors for Endocrine-Resistant ER+ Breast Cancer Fanning, Sean W.; Greene, Geoffrey L. Endocrinology, Vol. 160, Issue 4 https://doi.org/10.1210/en.2018-01095	journal	February 2019
Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents Sabbah, Dima A.; Ibrahim, Ameerah H.; Talib, Wamidh H. Medicinal Chemistry, Vol. 15, Issue 4 https://doi.org/10.2174/1573406414666180912111846	journal	May 2019

Similar Records

Species-specific pharmacology of antiestrogens: role of metabolism

Journal Article · Tue Mar 31 23:00:00 EST 1987 · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) · OSTI ID:6924617

Radiobrominated triphenylethylenes as estrogen receptor binding radiopharmaceuticals

Conference · Wed May 01 00:00:00 EDT 1985 · J. Nucl. Med.; (United States) · OSTI ID:7030645

Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation

Journal Article · Mon Feb 01 23:00:00 EST 2016 · eLife · OSTI ID:1628844

Related Subjects

60 APPLIED LIFE SCIENCES
Breast cancer
Drug development

Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

Citation Formats

References (42)

Cited By (4)

Similar Records

Related Subjects