Small molecule inhibitors of STAT3 with anti-tumor activity
The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growth in vitro or in vivo, e.g., as anti-cancer agents for treatment of cancer, such as breast cancer. The compounds of the invention include, but are not limited to, NSC 74859 (S3I-201), NSC 42067, NSC 59263, NSC 75912, NSC 11421, NSC 91529, NSC 263435, and pharmaceutically acceptable salts and analogs of the foregoing. Other non-malignant diseases characterized by proliferation of cells that may be treated using the compounds of the invention, but are not limited to, cirrhosis of the liver; graft rejection; restenosis; and disorders characterized by a proliferation of T cells such as autoimmune diseases, e.g., type 1 diabetes, lupus and multiple sclerosis. The invention further includes an in-vitro screening test for the presence of malignant cells in a mammalian tissue; a method of identifying inhibitors of constitutive Stat3 activation, Stat3-DNA binding, Stat5-DNA binding, and/or Stat3 dimerization; and a method of identifying anti-cancer agents.
1. A method of treating a subject that has a proliferation disorder, comprising administering an effective amount of an isolated compound to a subject, wherein the isolated compound is at least one compound selected from
wherein for the compound of formula C, formula D, formula E, or formula F:
R 1 is an aliphatic or aromatic group;
R 2 is an aliphatic or aromatic group;
each X is independently CO, SO 2 , CONH, or alkyl; and
Z is alkyl; and
the phosphotyrosine mimic is CO 2 H, SO 3 H, PO 3 H, NO 2 , CH 2 CO 2 H, or CF 2 CO 2 H
or a pharmaceutically acceptable salt or analog of any of the foregoing.
2. The method of claim 1 , wherein the proliferation disorder is cancer.
3. The method of claim 2 , wherein the compound is administered locally at the site of a tumor.
4. The method of claim 1 , wherein the proliferation disorder is cancer, and wherein the subject is suffering from a tumor and the compound inhibits growth of the tumor.
5. The method of claim 1 , wherein the proliferation disorder is a non-malignant disease characterized by aberrant Stat3 activation of cells.
6. The method of claim 1 , wherein the compound is administered locally at the site of the proliferation disorder.
7. The method of claim 1 , wherein the route of administration is selected from the group consisting of intravenous, intramuscular, oral, and intra-nasal.
8. The method of claim 1 , wherein the subject is human.
9. The method of claim 1 , wherein the subject is a non-human mammal.
10. The method of claim 1 , further comprising identifying the subject as one suffering from the proliferation disorder.
11. The method of claim 1 , wherein the subject is suffering from a tumor and wherein said administering comprises administering at the site of the tumor the compound:
or a pharmaceutically acceptable salt or analog thereof.
12. The method according to claim 1 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the R 1 group is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cylcoalkenyl, heterocycloalkenyl, acyl, or aryl, any of which may be optionally substituted.
13. The method according to claim 1 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the R 2 group is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cylcoalkenyl, heterocycloalkenyl, acyl, or aryl, any of which may be optionally substituted.
14. The method according to claim 1 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the R 1 group is aryl, substituted aryl, heteroaryl, or alkyl.
15. The method according to claim 1 , wherein for the compound of any of formula C, formula D, formula E, or formula F, the R 2 group is aryl, substituted aryl, heteroaryl, or alkyl.
16. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt or analog thereof.