Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer

Tria, George S.; Abrams, Tinya; Baird, Jason; Burks, Heather E.; Firestone, Brant; Gaither, L. Alex; Hamann, Lawrence G.; He, Guo; Kirby, Christina A.; Kim, Sunkyu; Lombardo, Franco; Macchi, Kaitlin J.; McDonnell, Donald P.; Mishina, Yuji; Norris, John D.; Nunez, Jill; Springer, Clayton; Sun, Yingchuan; Thomsen, Noel M.; Wang, Chunrong; Wang, Jianling; Yu, Bing; Tiong-Yip, Choi-Lai; Peukert, Stefan

doi:10.1021/acs.jmedchem.7b01682

Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer

Journal Article · Thu Mar 22 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b01682· OSTI ID:1545839

^[1]; Abrams, Tinya ^[1]; Baird, Jason ^[1]; ^[1]; Firestone, Brant ^[1]; Gaither, L. Alex ^[1]; Hamann, Lawrence G. ^[1]; He, Guo ^[1]; Kirby, Christina A. ^[1]; Kim, Sunkyu ^[1]; Lombardo, Franco ^[1]; Macchi, Kaitlin J. ^[1]; McDonnell, Donald P. ^[2]; Mishina, Yuji ^[1]; Norris, John D. ^[2]; Nunez, Jill ^[1]; Springer, Clayton ^[1]; Sun, Yingchuan ^[1]; Thomsen, Noel M. ^[1]; Wang, Chunrong ^[1] more »

Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States)
Duke Univ. School of Medicine, Durham, NC (United States)

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. Here, we describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Industrial Macromolecular Crystallography Association; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1545839

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 7 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (26)

Prognostic effect of estrogen receptor status across age in primary breast cancer Bentzon, Niels; Düring, Maria; Rasmussen, Birgitte Bruun International Journal of Cancer, Vol. 122, Issue 5 https://doi.org/10.1002/ijc.22892	journal	October 2007
Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor Bhatnagar, A. S.; Häusler, A.; Schieweck, K. The Journal of Steroid Biochemistry and Molecular Biology, Vol. 37, Issue 6 https://doi.org/10.1016/0960-0760(90)90460-3	journal	December 1990
Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated Transcription Shang, Yongfeng; Hu, Xiao; DiRenzo, James Cell, Vol. 103, Issue 6 https://doi.org/10.1016/S0092-8674(00)00188-4	journal	December 2000
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
Fulvestrant Revisited: Efficacy and Safety of the 500-mg Dose Howell, Anthony; Sapunar, Francisco Clinical Breast Cancer, Vol. 11, Issue 4 https://doi.org/10.1016/j.clbc.2011.02.002	journal	August 2011
Efficient synthesis of 3-oxygenated benzothiophene derivatives Zhang, Fuyao; Mitchell, David; Pollock, Patrick Tetrahedron Letters, Vol. 48, Issue 13 https://doi.org/10.1016/j.tetlet.2007.01.141	journal	March 2007
Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts Lai, Andiliy; Kahraman, Mehmet; Govek, Steven Journal of Medicinal Chemistry, Vol. 58, Issue 12 https://doi.org/10.1021/acs.jmedchem.5b00054	journal	March 2015
Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer Burks, Heather E.; Abrams, Tinya; Kirby, Christina A. Journal of Medicinal Chemistry, Vol. 60, Issue 7 https://doi.org/10.1021/acs.jmedchem.6b01468	journal	March 2017
3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic Acid: A Non-Steroidal Estrogen with Functional Selectivity for Bone over Uterus in Rats Willson, Timothy M.; Henke, Brad R.; Momtahen, Tanya M. Journal of Medicinal Chemistry, Vol. 37, Issue 11 https://doi.org/10.1021/jm00037a002	journal	May 1994
Torsionally and hydrophobically modified 2,3-diarylindenes as estrogen-receptor ligands Anstead, Gregory M.; Peterson, Chad S.; Pinney, Kevin G. Journal of Medicinal Chemistry, Vol. 33, Issue 10 https://doi.org/10.1021/jm00172a008	journal	October 1990
Benzothiophene Selective Estrogen Receptor Modulators with Modulated Oxidative Activity and Receptor Affinity Qin, Zhihui; Kastrati, Irida; Chandrasena, R. Esala P. Journal of Medicinal Chemistry, Vol. 50, Issue 11 https://doi.org/10.1021/jm070079j	journal	May 2007
Structure−Activity Relationships of Selective Estrogen Receptor Modulators: Modifications to the 2-Arylbenzothiophene Core of Raloxifene Grese, Timothy A.; Cho, Stephen; Finley, Don R. Journal of Medicinal Chemistry, Vol. 40, Issue 2 https://doi.org/10.1021/jm9606352	journal	January 1997
The p-(methylsulfinyl)benzyl group: a trifluoroacetic acid (TFA)-stable carboxyl-protecting group readily convertible to a TFA-labile group Samanen, James M.; Brandeis, Ester The Journal of Organic Chemistry, Vol. 53, Issue 3 https://doi.org/10.1021/jo00238a016	journal	February 1988
Bioactivation of the Selective Estrogen Receptor Modulator Desmethylated Arzoxifene to Quinoids: 4‘-Fluoro Substitution Prevents Quinoid Formation Liu, Hong; Liu, Ju; van Breemen, Richard B. Chemical Research in Toxicology, Vol. 18, Issue 2 https://doi.org/10.1021/tx049776u	journal	February 2005
Contrasting Endocrine Activities of cis and trans Isomers in a Series of Substituted Triphenylethylenes Harper, M. J. K.; Walpole, A. L. Nature, Vol. 212, Issue 5057 https://doi.org/10.1038/212087a0	journal	October 1966
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
Aromatase inhibitors for breast cancer: lessons from the laboratory Johnston, Stephen R. D.; Dowsett, Mitch Nature Reviews Cancer, Vol. 3, Issue 11 https://doi.org/10.1038/nrc1211	journal	November 2003
Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond Deblois, Geneviève; Giguère, Vincent Nature Reviews Cancer, Vol. 13, Issue 1 https://doi.org/10.1038/nrc3396	journal	November 2012
Mechanisms of aromatase inhibitor resistance Ma, Cynthia X.; Reinert, Tomás; Chmielewska, Izabela Nature Reviews Cancer, Vol. 15, Issue 5 https://doi.org/10.1038/nrc3920	journal	April 2015
Induced protein degradation: an emerging drug discovery paradigm Lai, Ashton C.; Crews, Craig M. Nature Reviews Drug Discovery, Vol. 16, Issue 2 https://doi.org/10.1038/nrd.2016.211	journal	November 2016
A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer Goss, Paul E.; Ingle, James N.; Martino, Silvana New England Journal of Medicine, Vol. 349, Issue 19 https://doi.org/10.1056/NEJMoa032312	journal	November 2003
Syntheses and Substituent Effects on the Properties of Unsymmetrical Photochromic Diarylethenes Bearing a Benzothiophene Unit Pu, Shouzhi; Li, Min; Liu, Gang Australian Journal of Chemistry, Vol. 62, Issue 5 https://doi.org/10.1071/CH08289	journal	January 2009
Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Down-regulators Wittmann, Bryan M.; Sherk, Andrea; McDonnell, Donald P. Cancer Research, Vol. 67, Issue 19 https://doi.org/10.1158/0008-5472.CAN-07-1590	journal	October 2007
Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for Advanced Breast Cancer: Results From the FIRST Study Robertson, John F. R.; Llombart-Cussac, Antonio; Rolski, Janusz Journal of Clinical Oncology, Vol. 27, Issue 27 https://doi.org/10.1200/JCO.2008.21.1136	journal	September 2009
Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer Di Leo, Angelo; Jerusalem, Guy; Petruzelka, Lubos Journal of Clinical Oncology, Vol. 28, Issue 30 https://doi.org/10.1200/JCO.2010.28.8415	journal	October 2010
Tamoxifen Resistance in Breast Cancer Chang, Min-Sun Biomolecules and Therapeutics, Vol. 20, Issue 3 https://doi.org/10.4062/biomolther.2012.20.3.256	journal	May 2012

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The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells Fanning, Sean W.; Jeselsohn, Rinath; Dharmarajan, Venkatasubramanian eLife, Vol. 7 https://doi.org/10.7554/elife.37161	journal	November 2018
Nickel‐Catalyzed 1,1‐Difluoroethylation of (Hetero)aryl Halides with 1,1‐Difluoroethyl Chloride (CH ₃ CF ₂ Cl) Liu, Jianchang; Zhang, Jida; Li, Xiangye Asian Journal of Organic Chemistry, Vol. 9, Issue 3 https://doi.org/10.1002/ajoc.202000004	journal	November 2019
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
GLL398, an oral selective estrogen receptor degrader (SERD), blocks tumor growth in xenograft breast cancer models Guo, Shanchun; Zhang, Changde; Mottamal, Madhusoodanan Breast Cancer Research and Treatment, Vol. 180, Issue 2 https://doi.org/10.1007/s10549-020-05558-w	journal	February 2020
1,1-Difluoroethyl chloride (CH ₃ CF ₂ Cl), a novel difluoroalkylating reagent for 1,1-difluoroethylation of arylboronic acids Liu, Jianchang; Zhang, Jida; Wu, Chaolin RSC Advances, Vol. 9, Issue 49 https://doi.org/10.1039/c9ra06406k	journal	January 2019
Cardiac arrhythmia considerations of hormone cancer therapies Barber, Mary; Nguyen, Lee S.; Wassermann, Johanna Cardiovascular Research, Vol. 115, Issue 5 https://doi.org/10.1093/cvr/cvz020	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

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