Compounds and methods for selectively targeting tumor-associated mucins
The present invention relates to pharmaceutical compositions containing tumor-selective targeted inhibitor glycoconjugates. These bioconjugates are ALK5 inhibitors covalently bound to biocompatible carrier molecules which selectively target and specifically bind to Muc4 that is overexpressed on a variety of tumor cell types. The ALK5 inhibitors are conjugated to tumor targetable glycans through a covalent linker. Preferably the acid-labile linker is designed to be stable in plasma and releases pharmacologically active inhibitors through acid-catalyzed hydrolysis in the acidic environment of the target tumor where the inhibitor activity is restored. Because the glycoconjugates are stable at physiological pH and in plasma, they advantageously reduce undesirable systemic ALK5 inhibitor activity; however, the preferable glycoconjugates are acid-labile conjugates that can be hydrolyzed upon reaching the more acid environment of the tumor.
1. A method for treating a subject having breast cancer, ovarian cancer, or pancreatic cancer in need of therapy thereof comprising administering to the subject a compound in an amount effective in reducing the migration or metastatic dissemination of mesenchymal tumor cells, said compound having the formula
or a compound having the formula
or a compound having the formula
where R is an alkyl, Y=0 or 1, R1, R2 and R3 are independently hydrogen, alkyl, aryl, aralkyl or cycloalkyl, R4 is independently hydrogen or lower alkyl, n is an integer from 1 to 6, Z is a linker, X is 0 or 1, R5 is hydrogen or a pharmacologically active residue of an ALK5 inhibitor, with the proviso said compound contains at least one pharmacologically active residue of an ALK5 inhibitor; and pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and diluents.
2. A method for treating a subject having a breast cancer, ovarian cancer, or pancreatic cancer in need of therapy thereof comprising administering to the subject a TGF-β ALK5 inhibitor-glycoconjugate in an amount effective in reducing the migration, extravasation or metastatic dissemination of mesenchymal tumor cells; wherein said TGF-β ALK5 inhibitor-glycoconjugate is a compound having the formula
or a compound having the formula
where R is an alkyl, Y=0 or 1, R1, R2 and R3 are independently hydrogen, alkyl, aryl, aralkyl or cycloalkyl, R4 is independently hydrogen or lower alkyl, n is an integer from 1 to 6, Z is a linker, X is 0 or 1, R5 is a pharmacologically active residue of an ALK5 inhibitor; and pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and diluents.
3. A method for treating a subject having a breast cancer, ovarian cancer, or pancreatic cancer in need of therapy thereof comprising administering to the subject a compound in an amount effective in reducing the migration or metastatic dissemination of mesenchymal tumor cells, said compound having the formula
where R is an alkyl, Y=0 or 1, R1, R2 and R3 are independently hydrogen, alkyl, aryl, aralkyl or cycloalkyl, R4 is hydrogen or lower alkyl, Z is a linker, X is 0 or 1, R5 is a pharmacologically active residue of an ALK5 inhibitor and pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and diluents.
4. The method of claim 3 wherein R5 of the compound is a residue of formula
where R6 is hydrogen or a lower alkyl having from 1 to 5 carbon atoms, R7 is hydrogen or lower alkyl having from 1 to 5 carbon atoms and R8 is an amide, nitrile, alkynyl having from 1 to 3 carbon atoms, carboxyl or alkanol group having from 1 to 5 carbon atoms, A is a direct bond or an alkyl having from 1 to 5 carbon atoms and B is a direct bond or an alkyl having from 1 to 5 carbon atoms.
5. The method of claim 3 wherein R5 of the compound is a residue of one of the following ALK5 inhibitors:
4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl)benzamide;
3-((4-(benzo[d][1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-((4-(benzo[d][1,3]dioxol-5-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl)benzamide;
4-((4-(3a,4-dihydrobenzo[d][1,3]dioxol-5-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-(4-(3a,4-dihydrobenzo[d][1,3]dioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl)benzoic acid;
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl)benzamide;
4-((4-(benzo[d][1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl)benzoic acid;
3-((4-(benzo[d][1,3]dioxol-5-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzamide;
3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide;
4-((5-(6-ethylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-1)methylamino)benzamide;
4-((5-(6-methylpyridin-2-yl)-4-(1,4,4a,8a-tetrahydroquinoxalin-6-yl)-1H-imidazol-2-yl)methylamino)benzamide;
4-((5-(6-ethylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-1)methylamino)benzamide;
3-((5-(6-ethylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-1)methylamino)benzamide;
3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide;
4-((5-(6-ethylpyridin-2-yl)-4-(1,4,4a,8a-tetrahydroquinoxalin-6-yl)-1H-imidazol-2-yl)methylamino)benzamide;
3-((5-(6-methylpyridin-2-yl)-4-(1,5-naphthyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzamide;
3-((3-(6-methylpyridin-2-yl)-4-(1,5-naphthyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzamide;
3-((3-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-pyrazol-1-yl)methyl)benzamide;
3-((4-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-pyrazol-1-yl)methyl)benzamide;
4-[5-benzo[1,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicylo[2.2.2.]octane-1-carboxylic acid amide;
4-[5-benzo[1,3]dioxol-5-yl-4-(6-ethyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicylo[2.2.2]octane-1-carboxylic acid amide;
4-[5-benzo[1,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicylo[2.2.2.]octane-1-carboxylic acid; or
4-[5-benzo[1,3]dioxol-5-yl-4-(6-ethyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicylo[2.2.2.]octane-1-carboxylic acid.