Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX-XXX
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Selective Estrogen Receptor Degraders (SERDs): A Promising Treatment to Overcome Resistance to Endocrine Therapy in ERα-Positive Breast Cancer Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
6,7-Dihydro-5H-benzo[7]annulene Derivatives as Estrogen Receptor Modulators
Patent Application Number:
WO 2017/140669 A1
Publication date:
24 August 2017
Priority Application:
EP 16305174.1
Priority date:
15 February 2016
Inventors:
Bouaboula, M.; Brollo, M.; Certal, V.; El-Ahmad, Y.; Filoche-Romme, B.; Halley, F.; Mccort, G.; Schio, L.; Tabart, M.; Terrier, C.; Thompson, F.
Applicants:
SANOFI [FR/FR]; 54 me La Boetie, 75008 Paris (FR).
Disease Area:
Breast cancer
Summary:
The invention in this patent application relates to 6,7-dihydro-5H-benzo[7]annulene derivatives represented generally by formula I. These compounds are selective antagonists of estrogen receptor modulators and may thus have utility as a treatment for breast cancer.
Biological Target:
Estrogen Receptor ERα
Estrogen receptors (ERs) are ligand-activated transcription factors that are members of the steroid/nuclear receptor superfamily. This family is involved in the regulation of gene expression, cellular proliferation, and differentiation in target tissues. ERs are activated by the hormone estrogen (17β-estradiol) and exist in two forms: ERα (encoded by the ESR1 gene) and ERβ (encoded by the ESR2 gene). ERs are mostly located in the cytosol of the cell; however, when they bind to the hormone estrogen, they translocate from the cytosol into the nucleus of the cell. There, they form dimers and bind to specific genomic sequences called estrogen response elements (ERE) to form DNA/ER complexes. A DNA/ER complex interacts with coregulators to modulate the transcription of target genes. ERα is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone, and white adipose tissue. Abnormalities in ERα signaling may lead to the development of cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases, and osteoporosis. Researchers have observed that ERα is typically expressed in about 10% of normal breast epithelium. However, this ratio surges to 50−80% in breast tumors. Hence, the name “ERα-positive breast tumors” is used to describe them. The involvement of estrogen in breast cancer is well established, and the modulation of ERα signaling is a standard treatment for the majority ERα-positive breast tumors. There currently exist several therapies that function by inhibiting the estrogen axis in breast cancer patients, including:
1.
Aromatase inhibitors (AIs): Aromatase is the enzyme that catalyzes the biosynthesis of estrogen. Since breast and ovarian cancers require estrogen to grow, thus, the AIs that can block estrogen synthesis and its action on receptors have been used to treat these forms of cancer. AIs are currently in use to treat early and advanced ERα-positive breast cancers in women, gynecomastia (a noncancerous increase in the size breast tissue) in men, and as a form of chemoprevention in high risk women. 2. Tamoxifen: an antagonist of the estrogen ligand binding to ERα. It is used to treat ERα-positive breast cancer in pre- and postmenopausal women. 3. Fulvestrant: An antagonist and downregulator of ER. It is a selective estrogen receptor degrader (SERD) that is used to treat breast cancer, particularly cases that have progressed despite initial treatment with endocrine therapies such as tamoxifen or aromatase inhibitors. Fulvestrant is currently in use as a treatment of hormone receptor positive metastatic breast cancer and locally advanced unresectable cancer in postmenopausal women. While endocrine (a.k.a. hormonal) therapies have contributed significantly to the successful treatment of breast cancer, still more than one-third of ERα-positive patients can display or develop resistance to these therapies over time. Researchers have postulated several mechanisms to explain the occurrence of such resistance, including:
• • •
Development of hypersensitivity of ERα to low estrogen level resulting from treatment with AIs. A switch in tamoxifen activity from antagonist to agonist during treatments with tamoxifen. Evidence obtained from preclinical and clinical studies suggests the involvement of the growth factor receptor signaling pathways in endocrine resistance and stimulation of cancer growth. These signaling pathways may stimulate cancer growth independently or in concert with ER signaling. • Acquired mutations in ERα can occur following hormonal therapy. Certain mutations may contribute to cancer progression and to failure of the endocrine therapy. Since most of the endocrine therapy resistance mechanisms rely on ERα-dependent activity, therefore, shutting down the ERα signaling would be a desirable strategy to overcome this resistance. This may be achieved by removing ERα from the tumor cells by using selective estrogen receptor degraders (SERDs). Clinical and preclinical data showed that treatment of cancer patients with SERDs is useful in circumventing a significant number of the resistance pathways.
Received: October 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00424 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
While there are several SERDs known in the art, there is still a need for the discovery and development of more effective SERDs with good degradation efficacy. The compounds of formula I described in this patent application are selective estrogen receptor degraders (SERDs) and may potentially provide a useful treatment for different forms of cancer including breast, ovarian, endometrial, prostate, uterine, cervical, and lung cancers. Important Compound Classes:
Key Structures:
The inventors described the structures and methods of synthesis of 219 examples of formula I including the following representative examples:
Biological Assay:
The following tests were carried out to determine the antagonist and degradation effects of the compounds of formula I on estrogen receptors: Test A: Biochemical antagonist activity on wild type (WT) and mutant estrogen receptors Test B: Cell proliferation/viability assay on MCF7 (breast tumor cells) WT and mutant cell lines Test C: Estrogen receptor degradation activity
Biological Data:
The following two tables list the results from testing the above representative examples:
B
DOI: 10.1021/acsmedchemlett.7b00424 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Recent Review Articles:
Patent Highlight
1. Nathan, M. R.; Schmid, P. Oncology and therapy 2017, 5 (1), 17−29. 2. Ohno, S. Clin. Breast Cancer 2016, 16 (4), 238−46. 3. Govek, S. P.; Nagasawa, J. I.; Douglas, K. L.; Lai, A. G.; Kahraman, M.; Bonnefous, C.; Aparicio, A. M.; Darimont, B. D.; Grillot, K. L.; Joseph, J. D.; et al. Bioorganic Med. Chem. Lett. 2015, 25 (22), 5163−5167. 4. Fan, W.; Chang, J.; Fu, P. Future Med. Chem. 2015, 7 (12), 1511−1519.
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5. Chlebowski, R. T. Clin. Investig. (London) 2014, 4 (1), 19−33.
AUTHOR INFORMATION
Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00424 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
