RUNX2 transcription factor inhibitors and uses thereof
Inventors
Passaniti, Antonino • Alexander, JR., MacKerell D.
Assignees
US Department of Veterans Affairs
Publication Number
US-10329246-B2
Publication Date
2019-06-25
Expiration Date
2036-03-18
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Abstract
Provide herein are compounds with a general chemical structure of: Substituents R1 and R2 independently are H, Cl, F, Br, CH3, CF3, SH, —N(C1-3alkyl)2, —NHC(O)C1-3alkyl, or —NHC(O)C5-7cycloalkyl, substituent R3 is H or C1-3 alkyl and R4 is a bridged cycloalkene such as a bridged cyclohexene or a bridge-substituted cyclohexene. The compounds are therapeutics to treat a cancer, such as breast cancer, or metastatic cancers, to inhibit RUNX2 activity, such as protein expression, in a cancer cell and to increase survival of a subject with breast cancer.
Core Innovation
The invention provides compounds with a general chemical structure characterized by substituents R1 and R2 independently being H, Cl, F, Br, CH3, CF3, SH, —N(C1-3alkyl)2, —NHC(O)C1-3alkyl, or —NHC(O)C5-7cycloalkyl, R3 being H or C1-3 alkyl, and R4 being a bridged cycloalkene such as a bridged cyclohexene or a bridge-substituted cyclohexene. These compounds act as therapeutics to treat cancers, including breast cancer and metastatic cancers, by inhibiting RUNX2 transcription factor activity, including inhibition of RUNX2 protein expression in cancer cells, thereby increasing survival of subjects with breast cancer.
RUNX2 is a transcription factor expressed in early stage ER+ breast cancer at levels above normal breast epithelia and promotes osteomimetic phenotype and metastasis to bone via transcriptional activation of genes such as osteopontin, matrix metalloproteinases, and VEGF. RUNX2 binding partners YAP and TAZ promote cell transformation and osteogenesis, with TAZ implicated in breast cancer progression including migration, invasion, tumorigenesis, drug resistance, and promotion of epithelial-mesenchymal transition. RUNX2 and TAZ are associated with mediating metastasis to bone, but their cooperative role in breast cancer had not been reported prior to this invention.
Despite advances in treating breast cancer, current modalities are insufficient to eradicate heterogeneous tumors such as luminal breast cancer that show high relapse rates and often metastasize to bone. There is a recognized need for inhibitors of RUNX2 as cancer therapeutics, as the prior art lacks such inhibitors or their derivatives and related cancer treatments. The present invention addresses this need by providing RUNX2 inhibitor compounds, pharmaceutical compositions including them, and methods for treating cancers via inhibition of RUNX2 activity.
Claims Coverage
The claims of the patent focus on methods of treating breast cancer and metastatic cancers using specific compounds that inhibit RUNX2 activity. There are multiple independent claims relating to these treatment methods.
Methods for treating breast cancer and metastatic cancer using defined compounds
Methods comprising administering to a subject a therapeutically effective dose of one or more compounds having specified chemical structures characterized by substituents R1, R2, R3, and R4, which inhibit RUNX2 activity and treat breast cancer or metastatic cancer originating from breast cancer.
Co-administration with other cancer drugs
The methods further comprise co-administration of one or more other cancer drugs such as Herceptin, Lapatinib, or E-Cadherin monoclonal antibody (DECMA1) to enhance therapeutic effects.
Specific chemical structures of therapeutically active compounds
Use of compounds with chemical structures where R1 and R2 substituents independently may be H, Cl, Br, or —NHC(O)CH3, R3 is H, and R4 is a bridged cyclohexene or bridge-substituted cyclohexene, and related substituent variants, for treating breast cancer or metastatic cancer.
Treatment inhibiting metastasis and metastases of breast cancer
Methods wherein the breast cancer comprises metastases and treatment aims to inhibit metastasis of breast cancer through administration of the inventive compounds.
The independent claims cover methods of treating breast cancer, metastatic cancers derived therefrom, co-administration with other cancer drugs, and specific chemical compound structures that inhibit RUNX2 to achieve therapeutic benefits.
Stated Advantages
The compounds selectively inhibit breast cancer cell growth and survival while showing less cytotoxicity to non-malignant cells.
They inhibit tumorsphere formation, anchorage-independent growth, and invasiveness of breast cancer cells, implicating a role in preventing metastasis.
Compound 1 and its analogs specifically inhibit RUNX2 transcriptional activity and downstream target gene expression without affecting non-RUNX family transcription factors.
Treatment with the compounds modulates glucose metabolism and mitochondrial activities in breast cancer cells, suggesting metabolic targeting.
In vivo administration delays tumor onset, reduces tumor burden and metastasis, and shows efficacy in patient-derived tumor xenografts without significant toxicity.
Combination therapy with CDK inhibitors enhances sensitivity and reduces breast cancer cell proliferation more effectively than either agent alone.
Documented Applications
Treatment of breast cancer, including estrogen receptor-positive luminal breast cancer.
Treatment of metastatic cancers, including metastatic breast cancer and metastases originating from breast, lung, melanoma, colorectal, prostate, or pancreatic cancers.
Use in pharmaceutical compositions for inhibition of RUNX2 to treat diverse cancers such as osteosarcoma, ovarian cancer, prostate cancer, melanoma, Ewing sarcoma, pancreatic cancer, thyroid cancer, leukemia, head/neck cancer, colorectal cancer, liver cancer, lung cancer, pituitary cancer, gliomas, esophageal cancer, and multiple myeloma.
Combination therapy with known cancer drugs like Herceptin, Lapatinib, and DECMA1 antibody to improve cancer treatment outcomes.
Use to inhibit tumorsphere formation, anchorage-independent growth, and cell invasiveness in vitro as models of cancer progression and metastasis.
Use in preclinical animal models including transgenic MMTV-PyMT mice and patient-derived xenograft (PDX) models to demonstrate suppression of tumor growth and metastasis.
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