Daidzein analogs as treatment for cancer
Inventors
Wang, Guangdi • Burow, Matthew E. • Boue, Stephen M. • Wiese, Thomas E. • Jiang, Quan
Assignees
Tulane University • US Department of Agriculture USDA • Xavier University of Louisiana
Publication Number
US-9669004-B2
Publication Date
2017-06-06
Expiration Date
2031-07-08
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Abstract
Provided are compositions for treatment of cancers, including breast cancer, comprising at least one novel daidzein analog, as well as methods of using the same for preventing or treating cancer or tumor growth.
Core Innovation
The invention provides novel daidzein analogs that exhibit inhibitory effects on cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor-regulated progesterone receptor gene expression. These analogs are useful in the prevention and treatment of estrogen receptor positive breast cancer, and compositions comprising these analogs are effective in minimizing or preventing cancer growth, including breast cancer and other cancers involving aberrant activation of the PI3K/AKT/mTOR pathway.
The problem being addressed is the high incidence and mortality rate of breast cancer and the limitations of current treatments, including resistance to chemotherapy and endocrine therapy. Tamoxifen, a selective estrogen receptor modulator (SERM) used in treatment, has side effects such as promoting uterine cancer risk and blood clots. There is a recognized need for new SERMs with better efficacy and safety profiles to treat estrogen receptor positive breast cancer effectively.
Claims Coverage
The patent includes two independent claims that cover pharmaceutical compositions comprising novel daidzein analogs and methods of minimizing or treating estrogen-dependent cancer using these analogs. The main inventive features involve specific daidzein analog structures and their reduced estrogenic activity compared to daidzein.
Pharmaceutical composition comprising specific daidzein analogs
The composition comprises at least one daidzein analog selected from a defined group of compounds, specifically including 3-(4-Hydroxyphenyl)-8,8-dimethyl-8H-pyrano[2,3-f]chromen-4-one and various 7-substituted chromen-4-one derivatives. These analogs are characterized by inducing less estrogenic activity than daidzein.
Method of minimizing or treating estrogen-dependent cancer
The method involves administering to an animal in need a composition comprising an effective amount of at least one of the specified daidzein analogs, which have reduced estrogenic activity compared to daidzein, for treating breast cancer.
Specific analog selection for compositions and methods
Dependent claims specify individual daidzein analog compounds from the group for use in compositions and methods, including the compound 3-(4-Hydroxyphenyl)-8,8-dimethyl-8H-pyrano[2,3-f]chromen-4-one as a preferred analog.
Product forms for administration
The compositions can be formulated for oral delivery forms such as dried powders, liquids, capsules, pellets, and pills, or for parenteral administration including intravenous, intradermal, intramuscular, and subcutaneous routes.
Inclusion of carriers and excipients in compositions
The pharmaceutical compositions may include additional components such as carriers, binders, diluents, excipients, or mixtures thereof to facilitate formulation and administration.
The independent claims comprehensively cover pharmaceutical compositions with specific novel daidzein analogs exhibiting reduced estrogenic activity and their use in methods to treat estrogen-dependent breast cancer, including various formulation and administration options.
Stated Advantages
The daidzein analogs exhibit potent antiestrogenic activity while minimizing estrogenic effects, offering potentially improved safety and efficacy over current SERMs like tamoxifen.
The analogs inhibit cancer cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor-regulated progesterone receptor gene expression, indicating effective therapeutic action against estrogen receptor positive breast cancer.
Analog 2 demonstrates anti-estrogenic effects in vitro and in vivo, reducing tumor volume comparably to tamoxifen and the pure anti-estrogen ICI 182,780.
The analogs, particularly analog 2, inhibit migration of triple-negative breast carcinoma cells, suggesting potential use as anti-metastatic agents.
The effects on triple-negative breast cancer may involve modulation of the PI3K/AKT/mTOR pathway, indicating a mechanism of action relevant to cancer treatment.
Documented Applications
Prevention and treatment of estrogen receptor positive breast cancer using compositions comprising novel daidzein analogs.
Treatment of other cancers involving aberrant activation of the PI3K/AKT/mTOR pathway, including gastric carcinoma, ovarian cancer, pancreatic cancer, stomach cancer, and non-small-cell lung cancer.
Use of analog 2 as a therapeutic agent to inhibit tumor growth and migration in breast cancer xenograft models and triple-negative breast carcinoma cell lines.
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