RUNX2 transcription factor inhibitors and uses thereof
Provide herein are compounds with a general chemical structure of: Substituents R 1 and R 2 independently are H, Cl, F, Br, CH 3 , CF 3 , SH, —N(C 1-3 alkyl) 2 , —NHC(O)C 1-3 alkyl, or —NHC(O)C 5-7 cycloalkyl, substituent R 3 is H or C 1-3 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.
1. A method for treating breast cancer in a subject, comprising:
administering to the subject a dose of one or more compounds having the chemical structure
wherein
R 1 and R 2 independently are H, Cl, F, Br, CH 3 , CF 3 , SH, —N(C 1-3 alkyl) 2 , —NHC(O)C 1-3 alkyl, or —NHC(O)C 5-7 cycloalkyl;
R 3 is H or C 1-3 alkyl; and
R 4 is
or
a pharmaceutically acceptable salt thereof effective to inhibit a RUNX2 activity, thereby treating the breast cancer.
2. The method of claim 1 , further comprising administering one or more other cancer drugs.
3. The method of claim 2 , wherein the other cancer drugs are Herceptin, Lapatinib, or E-Cadherin monoclonal antibody (DECMA1) antibody.
4. The method of claim 1 , wherein the breast cancer is a metastatic cancer.
5. A method for treating a metastatic cancer originating from a breast cancer in a subject, comprising:
administering to the subject a dose of one or more compounds having the chemical structure
wherein
R 1 and R 2 independently are H, Cl, F, Br, CH 3 , CF 3 , SH, —N(C 1-3 alkyl) 2 , —NHC(O)C 1-3 alkyl, or —NHC(O)C 5-7 cycloalkyl;
R 3 is H or C 1-3 alkyl; and
R 4 is
or
a pharmaceutically acceptable salt thereof effective to inhibit a RUNX2 activity, thereby treating the metastatic cancer.
6. The method of claim 5 , further comprising administering one or more other cancer drugs.
7. The method of claim 6 , wherein the other cancer drugs are Herceptin, Lapatinib, or E-Cadherin monoclonal antibody (DECMA1).
8. A method for treating breast cancer in a subject, comprising
administering to the subject a dose of a compound having the chemical structure:
or a pharmaceutically acceptable salt thereof effective to inhibit RUNX2, thereby treating the breast cancer.
9. The method of claim 8 , further comprising administering one or more other cancer drugs.
10. The method of claim 9 , wherein the other cancer drugs are Herceptin, Lapatinib, or E-Cadherin monoclonal antibody (DECMA1).
11. The method of claim 8 , wherein the breast cancer comprises metastases thereof.
12. The method of claim 8 , wherein treatment inhibits metastasis of the breast cancer.
13. The method of claim 1 , wherein R 3 is H.
14. The method of claim 1 , wherein R 1 and R 2 are independently H, Cl, Br, or —NHC(O)CH 3 , R 3 is H and R 4 is
15. The method of claim 1 , wherein R 1 and R 2 are independently H, Cl, CH 3 , —NHC(O)CH 3 , —NHC(O)cyclohexane, or N(CH 3 ) 2 , R 3 is H and R 4 is
16. The method of claim 1 , wherein R 1 and R 2 are each Cl and R 3 is H.
17. The method of claim 1 , wherein the chemical structure is:
18. The method of claim 5 , wherein R 3 is H.
19. The method of claim 5 , wherein R 1 and R 2 are independently H, Cl, Br, or —NHC(O)CH 3 , R 3 is H and R 4 is
20. The method of claim 5 , wherein R 1 and R 2 are independently H, Cl, CH 3 , —NHC(O)CH 3 , —NHC(O)cyclohexane, or N(CH 3 ) 2 , R 3 is H and R 4 is
21. The method of claim 5 , wherein R 1 and R 2 are each Cl and R 3 is H.
22. The method of claim 5 , wherein the chemical structure is: