STAT3 dimerization inhibitors
The subject matter disclosed herein relates to compositions and methods of making and using the compositions. In a further aspect, the subject matter disclosed herein relates to inhibitors of STAT3 dimerization. Methods of making these compositions as well as compositions comprising these compositions are also disclosed. Also disclosed are methods of treating or preventing certain cancers by administering to an individual in need thereof and effective amount of the compounds disclosed herein. Still further, disclosed herein are methods of inhibiting STAT3 by contacting a cell with a compound or composition as disclosed herein.
1. A compound having Formula I:
wherein
R 1 is H, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, benzyl, 4-piperidyl, 3-(4-pyridyl), pyridinyl, or
wherein R 4 is OH, Cl, F, Br, I, cyclohexyl, OC 1 -C 10 alkyl, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, pyridinyl, OPh, PO(OEt) 2 , or PO(OH) 2 ;
R 2 is
wherein X is O, NH, S, or CH 2 , and R 5 is H, OH, Cl, F, Br, I, cyclohexyl, or C 1 -C 10 alkyl;
R 3 is H, OH, Cl, F, Br, I, OC 1 -C 10 alkyl, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, NO 2 , NH 3 , or CN; and
R 6 is H, C 1 -C 10 alkyl, or a pharmaceutically acceptable counterion;
each Y is, independent of the others, CH or N; and
Z is C or N;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 is H, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, benzyl, 4-piperidyl, 3-(4-pyridyl), or pyridinyl.
3. The compound of claim 1 , wherein R 1 is
wherein each Y is CH, and R 4 is OH, Cl, F, Br, I, cyclohexyl, C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, pyridinyl, or OPh.
4. The compound of claim 1 , wherein R 1 is
wherein each Y is CH, and R 4 is cyclohexyl, C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, or pyridinyl.
5. The compound of claim 4 , wherein R 4 is cyclohexyl.
6. The compound of claim 1 , wherein R 5 is H, OH, Cl, F, Br, or I.
7. The compound of claim 1 , wherein X is O.
8. The compound of claim 1 , wherein R 2 is OPh.
9. The compound of claim 1 , wherein R 3 is H or OCH 3 .
10. The compound of claim 1 , wherein the compound is
11. The compound of claim 1 , wherein the compound has the formula
12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
13. A method of reducing or inhibiting tumor growth in an individual with cancer, comprising: administering a therapeutically effective amount of the compound of claim 1 to the individual, wherein the cancer is pancreatic cancer, breast cancer, lung cancer, prostrate cancer, ovarian cancer, colon cancer, gastric cancer, head and neck cancer, melanoma, leukemia, multiple myeloma or lypmpoma.
14. The method of claim 13 , wherein STAT3 is persistently tyrosine phosphorylated and constitutively activated in the cancer.
15. The method of claim 13 , wherein the compound is
16. A method of inhibiting STAT3-STAT3 dimerization and/or STAT3-EGFR binding in a cell, comprising: administering to the cell an effective amount of the compound of claim 1 to the cell.
17. The method of claim 13 , wherein the compound has the formula