Stat3 inhibitor having anti-cancer activity and methods
A small-molecule Stat3 dimerization inhibitor, S3I-M2001, is described and the dynamics of intracellular processing of activated Stat3 within the context of the biochemical and biological effects of the Stat3 chemical probe inhibitor are elucidated. S3I-M2001 is a newly-identified oxazole-based peptidomimetic of the Stat3 Src Homology (SH) 2 domain-binding phosphotyrosine peptide that selectively disrupts active Stat3:Stat3 dimers. Stat3-dependent malignant transformation, survival, and migration and invasion of mouse and human cancer cells harboring persistently-activated Stat3 were inhibited by S3I-M2001. S3I-M2001 inhibited Stat3-dependent transcriptional regulation of tumor survival genes, such as Bcl-xL. The disclosed compound is useful as a new potential treatment for certain cancers.
1. A compound, or a pharmaceutically acceptable salt thereof, having a structure represented by a formula:
2. A pharmaceutically acceptable composition containing the compound of claim 1 .
3. A pharmaceutically acceptable composition containing the compound of claim 1 in an effective amount for inhibiting Stat3 dimerization in a mammalian cell contacted with said composition.
4. A method of treating a mammalian cell having a dysfunctional Stat3 protein, the method comprising contacting the cell with the compound of claim 1 .
5. A method of treating a mammalian cell, the method comprising contacting the cell with the composition of claim 2 .
6. A method of treating a mammalian cell having a dysfunctional Stat3 protein, the method comprising contacting the cell with the composition of claim 2 .
7. A method of inhibiting a mammalian cell harboring constitutively active Stat3, the method comprising contacting the cell with an effective amount of the compound of claim 1 .
8. A method of treating a human breast cancer cell or pancreatic cancer cell, the method comprising contacting the cell with an effective amount of the compound of claim 1 to inhibit Stat3 activity therein.
9. A method of treating human breast or pancreatic cancer cells having a constitutively active level of Stat3, the method comprising administering a sufficient amount of the compound of claim 1 to contact said cancer cells.
10. A method of treatment effective to inhibit growth of a human breast cancer tumor cell, the method comprising administering to the cell a sufficient amount of the compound of claim 1 .
11. A method of inhibiting migration of a malignant cell, the method comprising contacting the cell with the compound of claim 1 .
12. A method of treating a mammalian cancer having a dysfunctional level of Stat3, the method comprising contacting the cancer with a therapeutically effective amount of the compound having a structure represented by a formula:
13. A method of treating a mammalian cancer having a dysfunctional Stat3 protein, the method comprising contacting the cancer with the compound having a structure represented by a formula:
14. A method of treating a human breast or pancreatic cancer cell, the method comprising contacting at least one cell of a human breast or pancreatic cancer with the composition of claim 2 .
15. A method of treating a mammalian cancer having a dysfunctional Stat3 protein, the method comprising contacting the cell with the composition of claim 2 .
16. A method of inhibiting a mammalian cancer having a constitutively active Stat3, the method comprising contacting the cancer with an effective amount of the compound of claim 1 .
17. A method of treating a human breast cancer or pancreatic cancer, the method comprising contacting the cancer with an amount of the compound of claim 1 effective to inhibit Stat3 activity therein.
18. A method of treating human breast or pancreatic cancer having a constitutively active level of Stat3, the method comprising administering a sufficient amount of the compound of claim 1 to contact said cancer.
19. A method of patient treatment effective for inhibiting growth of a human breast cancer tumor, the method comprising administering to the patient a sufficient amount of the compound of claim 1 to contact the cancer tumor.
20. A method of inhibiting migration of malignant cells from a mammalian cancer, the method comprising contacting the cells with the compound of claim 1 .
21. A method of inhibiting growth of a human breast or pancreatic cancer tumor, the method comprising contacting at least one cell of a human breast or pancreatic cancer tumor with the compound of claim 1 .