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US 6,552,055 B2Granted
Methods and pharmaceutical compositions for inhibiting tumor cell growth
AssigneeDana-Farber Cancer Institute, Inc.
InventorsBruce M. Spiegelman, Elisabetta Mueller, Pasha Sarraf, Soner Altiok, Peter Tontonoz, Samuel Singer
Life of this patent
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Abstract
The present invention is based on the finding that activation of PPARγ plays a key role in inducing growth arrest and differentiation of certain actively proliferating cells. We show that administration of PPARγ agonists, such as thiazolidinedione ligands (TZDs), is effective both in vitro and in vivo at inhibiting the proiferation of such cells.
Claims4
A method for inhibiting proliferation of a PPARγ-responsive hyperproliferative cell, comprising ectopically contacting the cell with a PPARγ agonist selected from the group consisting of:
- prostaglandin 15-deoxy-Δ12,14PGJ2, pioglitazone, troglitazone, BRL 49653, ciglitazone, englitazone, 5-[(2-alkoxy-5-pyridyl)methyl]-2,4-thiazolidinedione, 5-[(substituted-3-pyridyl)methyl]-2,4-thiazolidinedione, 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-dione, 5-[4-[3-(4-methoxyphenyl)-2-oxooxazolidin-5-yl]-methoxy]benzyl-2,4-thiazoli-dinedione, 5-[4-[3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl]-methoxy]benzyl-2,4-thiazolidinedione, 5-[4-[3-(4-chloro-2-fluorophenyl)-2-oxooxazolidin-5-yl]methoxy]benzyl-2,4-thiazolidinedione, 5-[4-[3-(4-trifluoromethoxyphenyl)-2-oxooxazolidin-5-yl]methoxy] benzyl-2,4-thiazolidinedione, 5-[4-[3-(4-trifluoromethylphenyl)-2-oxooxazolidin-5-yl]methoxy]benzyl-2,4-thiazolidinedione, 5-[4-[2-[3-(4-trifluoromethylphenyl)-2-oxooxazolidin-5-yl]ethoxy]benzyl]-2,4-thiazolidinedione, 5-[4-[2-[3-(4-chloro-2-fluorophenyl)-2-oxooxazolidin-5-yl]ethoxy]benzyl]-2,4-thiazolidinedione, 5-[4-[3-(4-pyridyl)-2-oxooxazolidin-5-yl]methoxy]-benzyl-2,4-thiazolidinedione, 4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide, 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-5-methylthiazolidine-2,4-dione, 5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione, 5-[4-[2-[N-methyl-N-(phenoxycarbonyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione, 5-[4-(2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione, 5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione, 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione, 5-[[4-(3-hydroxy-1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione, 5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadizolidione-2,4-dione, 5-[[2-(2-naphthylmethyl)benzoxazol]-5-ylmethyl]thiadiazoline-2,4-dione, 5-[4-[2-(3-phenylureido)ethoxyl]benzyl]thiadiazoline-2,4-dione, 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione, 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiadiazoline-2,4-dione, 5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]-oxazolidine-2,4-dione, 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione, and 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-oxazolidine-2,4-dione, in an amount effective to induce differentiation of the cell to a phenotype of lower proliferative index.
A method of treating or prophylactically preventing, in a subject animal, a disorder characterized by unwanted proliferation of PPARγ-responsive hyperproliferative cells, comprising administering to the animal a pharmaceutical preparation of a PPARγ agonist selected from the group consisting of:
- prostaglandin 15-deoxyΔ12,14PGJ2, pioglitazone, troglitazone, BRL 49653, ciglitazone, englitazone, 5-[(2-alkoxy-5-pyridyl)methyl]-2,4-thiazolidinedione, 5-[(substituted-3-pyridyl)methyl]-2,4-thiazolidinedione, 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-dione, 5-[4-[3-(4-methoxyphenyl)-2-oxooxazolidin-5-yl]-methoxy]benzyl-2,4-thiazoli-dinedione, 5-[4-[3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl]-methoxy]benzyl-2,4-thiazo-lidinedione, 5-[4-[3-(4-chloro-2-fluorophenyl)-2-oxooxazolidin-5-yl]methoxy]benzyl-2,4-thiazolidinedione, 5-[4-[3-(4-trifluoromethoxyphenyl)-2-oxooxazolidin-5-yl]methoxy] benzyl-2,4-thiazolidinedione, 5-[4-[3-(4-trifluoromethylphenyl)-2-oxooxazolidin-5-yl]methoxy]benzyl-2,4-thiazolidinedione, 5-[4-[2-[3-(4-trifluoromethylphenyl)-2-oxooxazolidin-5-yl]ethoxy]benzyl]-2,4-thiazolidinedione, 5-[4-[2-[3-(4-chloro-2-fluorophenyl)-2-oxooxazolidin-5-yl]ethoxy]benzyl]-2,4-thiazolidinedione, 5-[4-[3-(4-pyridyl)-2-oxooxazolidin-5-yl]methoxy]-benzyl-2,4-thiazolidinedione, 4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide, 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-5-methylthiazolidine-2,4-dione, 5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione, 5-[4-[2-[N-methyl-N-(phenoxycarbonyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione, 5-[4-(2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione, 5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione, 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione, 5-[[4-(3-hydroxy-1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione, 5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadizolidione-2,4-dione, 5-[[2-(2-naphthylmethyl)benzoxazol]-5-ylmethyl]thiadiazoline-2,4-dione, 5-[4-[2-(3-phenylureido)ethoxyl]benzyl]thiadiazoline-2,4-dione, 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione, 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiadiazoline-2,4-dione, 5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]-oxazolidine-2,4-dione, 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione, and 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-oxazolidine-2,4-dione, in an amount effective to inhibit growth of the PPARγ-responsive hyperproliferative cells.
Dependencies are inferred from the claim text.