STAT3 Inhibitors

Abstract

Small molecule inhibitors of Stat3 and their derivatives are disclosed. Also described are methods to inhibit cell growth by use of Stat3 inhibitors, and the use of Stat3 inhibitors for the prevention and/or treatment of cancer. Further, inhibitors of Stat3 that also do not inhibit Stat1 are described as well as their derivatives. Methods of screening additional compounds for Stat3 inhibition activity and/or non-inhibition of Stat1 activity are also described herein.

What is claimed is: 
     
         1 . A method of inhibiting Stat3 in a cell, comprising delivering to the cell an effective amount of a compound selected from the group consisting of 4-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxo-1-propen-1-yl]benzoic acid; 4 {5-[(3-ethyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-2-furyl}benzoic acid; 4-[({3-[(carboxymethyl)thio]-4-hydroxy-1-naphthyl}amino)sulfonyl]benzoic acid; 3-({2-chloro-4-[(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)methyl]-6-ethoxyphenoxy}methyl)benzoic acid; methyl 4-({[3-(2-methyoxy-2-oxoethyl)-4,8-dimethyl-2-oxo-2H-chromen-7-yl]oxy}methyl)benzoate; 4-chloro-3-{5-[(1,3-diethyl-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid; a functionally active derivative thereof and a mixture thereof. 
     
     
         2 . The method of  claim 1 , wherein the cell is in vivo in a mammal. 
     
     
         3 . The method of  claim 2 , wherein the mammal is a human. 
     
     
         4 . The method of  claim 3 , wherein the human is known, suspected, or at risk for developing cancer, a hyperproliferative disease, a chronic viral infection, pulminary fibrosis, myelofibrosis, or myelodysplastic syndrome, asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis, multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonary lymphangioleiomyomatosis, age-related macular degeneration or amyloidosis. 
     
     
         5 . The method of  claim 4 , wherein the human is known to have cancer and is receiving an additional therapy. 
     
     
         6 . The method of  claim 5 , wherein the additional therapy is chemotherapy, surgery, radiation, or a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein Stat1 is not inhibited by the compound. 
     
     
         8 . The method of  claim 1 , wherein the cell is a cancer stem cell. 
     
     
         9 . The method of  claim 8 , wherein the cancer stem cell is a leukemic stem cell. 
     
     
         10 . The method of  claim 8 , wherein the cancer stem cell is a breast cancer stem cell. 
     
     
         11 . A method of treating or preventing cancer in an individual, comprising administering to the individual a compound selected from the group consisting of 4{5-[(3-ethyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-2-furyl}benzoic acid; 4-[({3-[(carboxymethyl)thio]-4-hydroxy-1-naphthyl}amino)sulfonyl]benzoic acid; 3-({2-chloro-4-[(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)methyl]-6-ethoxyphenoxy}methyl)benzoic acid; methyl 4-({[3-(2-methyoxy-2-oxoethyl)-4,8-dimethyl-2-oxo-2H-chromen-7-yl]oxy}methyl)benzoate; 4-chloro-3-{5-[(1,3-diethyl-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid; a functionally active derivative thereof and a mixture thereof. 
     
     
         12 . The method of  claim 11 , wherein the individual is a human. 
     
     
         13 . The method of  claim 12 , wherein the human is known to have cancer, is suspected of having cancer, or is at risk for developing cancer. 
     
     
         14 . The method of  claim 12 , wherein the human is known to have cancer and is receiving an additional therapy. 
     
     
         15 . The method of  claim 14 , wherein the additional therapy is chemotherapy, surgery, radiation, or a combination thereof. 
     
     
         16 . A kit for the treatment of cancer, comprising a compound selected from the group consisting of 4{5-[(3-ethyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-2-furyl}benzoic acid; 4-[({3-[(carboxymethyl)thio]-4-hydroxy-1-naphthyl}amino)sulfonyl]benzoic acid; 3-({2-chloro-4-[(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)methyl]-6-ethoxyphenoxy}methyl)benzoic acid; methyl 4-({[3-(2-methyoxy-2-oxoethyl)-4,8-dimethyl-2-oxo-2H-chromen-7-yl]oxy}methyl)benzoate; 4-chloro-3-{5-[(1,3-diethyl-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid; a functionally active derivative thereof and a mixture thereof housed in a suitable container. 
     
     
         17 . The kit of  claim 16 , further comprising an additional cancer treatment.