RUNX2 transcription factor inhibitors and uses thereof
Inventors
Passaniti, Antonino • MacKerell, JR., Alexander D.
Assignees
US Department of Veterans Affairs
Publication Number
US-11634381-B2
Publication Date
2023-04-25
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 defined general chemical structure effective as inhibitors of the RUNX2 transcription factor. These compounds include specific substituents R1 and R2 independently selected from H, Cl, F, Br, CH3, CF3, SH, —N(C1-3alkyl)2, —NHC(O)C1-3alkyl, or —NHC(O)C5-7cycloalkyl, R3 as H or C1-3 alkyl, and R4 as a bridged cycloalkene such as a bridged cyclohexene or bridge-substituted cyclohexene. These compounds and related pharmaceutical compositions are used as therapeutics to treat cancers including breast cancer and metastatic cancers by inhibiting RUNX2 activity in cancer cells, thereby increasing survival of subjects with breast cancer.
The problem addressed by the invention is the insufficiency of current treatments for breast cancer, particularly luminal breast cancer which has high relapse rates often with bone metastasis. RUNX2 transcription factor is implicated in promoting breast cancer progression and metastasis through activation of pathways leading to cell proliferation, survival, invasion, and stem cell renewal characteristics. Prior art lacks suitable RUNX2 inhibitors or analog compounds and methods for effective cancer treatments targeting RUNX2 activity. This invention provides compounds that inhibit RUNX2 activity to address this unmet need in breast cancer therapy.
Claims Coverage
The patent contains five claims directed to pharmaceutical compositions comprising compounds effective to inhibit RUNX2 activity with specific chemical structures and substituent variations.
Pharmaceutical composition comprising RUNX2 inhibitory compounds
A pharmaceutical composition comprising a compound effective to inhibit RUNX2 activity in cancer cells, having the specified chemical structure with substituents R1, R2, R3, and R4 as defined in the patent.
Specific substituent R3 as hydrogen
The compound wherein the R3 substituent is hydrogen.
Specific substituents R1 and R2 as H, Cl, Br, or —NHC(O)CH3, R3 as H and defined R4 structure
A compound where R1 and R2 are independently selected from H, Cl, Br, or —NHC(O)CH3; R3 is H; and R4 is a specified bridged cyclohexene structure as described.
Specific substituents R1 and R2 as H, Cl, CH3, —NHC(O)CH3, —NHC(O)cyclohexane, or —N(CH3)2, R3 as H and defined R4 structure
A compound where R1 and R2 independently are H, Cl, CH3, —NHC(O)CH3, —NHC(O)cyclohexane, or —N(CH3)2; R3 is H; and R4 is a defined bridged cyclohexene structure.
Specific compound chemical structure
A pharmaceutical composition comprising a compound with the specific chemical structure of compound 1 (3-(N-(3,4-dichlorophenyl)carbamoyl)-5-norbornene-2-carboxylic acid) or its pharmaceutically acceptable salt.
The claims collectively cover pharmaceutical compositions containing specific RUNX2 inhibitory compounds characterized by precise chemical structures and substituent variants effective in cancer treatment by inhibiting RUNX2 activity.
Stated Advantages
The compounds exert potent inhibitory activity on RUNX2 transcription factor, thereby suppressing breast cancer cell growth, survival, invasion, and tumorsphere formation.
Compound 1 shows selective anti-proliferative effects with less cytotoxicity toward non-malignant cells.
Compound 1 inhibits RUNX2-mediated transcriptional activity and metastatic phenotype, decreasing expression of RUNX2 target genes involved in metastasis and glycolysis.
Compound 1 increases RUNX2 protein stability while inhibiting its activity, affecting cancer cell metabolism and signaling pathways.
The compound activates tumor suppressor Hippo pathway signaling, reducing nuclear localization of oncogenic cofactors like TAZ.
The compound effectively suppresses in vivo tumor growth and metastases with no significant adverse effects on animal health.
Combination therapy with compound 1 and CDK inhibitors enhances anti-cancer efficacy, overcoming drug resistance in breast cancer cells.
Documented Applications
Treatment of breast cancer, including luminal breast cancer expressing RUNX2.
Treatment of metastatic cancers originating from breast cancer, lung cancer, melanoma, colorectal cancer, prostate cancer, or pancreatic cancer.
Treatment of other cancers including 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.
Inhibition of RUNX2 activity in cancer cells to reduce cancer cell proliferation, invasion, metastasis, and tumorsphere formation.
Use in combination with other cancer drugs such as Herceptin, Lapatinib, or DECMA1 antibody for enhanced therapeutic effect.
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