Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer
| Autor: | Yuji Mishina, Jianling Wang, Choi-Lai Tiong-Yip, He Guo, Noel Marie-France Thomsen, Jill Nunez, Franco Lombardo, Clayton Springer, Jason Baird, L. Alex Gaither, John D. Norris, Sunkyu Kim, Brant Firestone, Stefan Peukert, Kaitlin J. Macchi, Donald P. McDonnell, Tinya Abrams, Chunrong Wang, Bing Yu, Lawrence G. Hamann, Yingchuan Sun, Burks Heather Elizabeth, Christina A. Kirby, George Scott Tria |
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| Rok vydání: | 2018 |
| Předmět: |
Selective Estrogen Receptor Modulators
0301 basic medicine Biological Availability Mice Nude Estrogen receptor Antineoplastic Agents Breast Neoplasms Thiophenes Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Drug Discovery medicine Animals Humans Endocrine system Rats Wistar Aromatase biology Fulvestrant Chemistry Estrogen Receptor alpha Cancer medicine.disease Xenograft Model Antitumor Assays Rats 030104 developmental biology Selective estrogen receptor modulator Drug Design 030220 oncology & carcinogenesis MCF-7 Cells biology.protein Cancer research Molecular Medicine Female Estrogen receptor alpha medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 61:2837-2864 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01682 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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