Anti-cancer compounds targeting ral gtpases and methods of using the same
AssigneeThe Regents of the University of Colorado, a body corporate
InventorsDan THEODORESCU, Michael Fitzpatrick WEMPE, David ROSS, Samy MEROUEH, Martin A. SCHWARTZ, Phillip REIGAN
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Abstract
The invention provides methods of inhibiting the growth or metastasis of a cancer in a mammal by inhibiting a Ral GTPase in the mammal. The invention also provides small molecule inhibitors of Ral GTPases useful in the methods of the invention and pharmaceutical compositions containing the therapeutically effective compounds of the invention, and methods of using the same.
Claims20
A compound having the structure:
- wherein:
- n=0-5;
- X, Y, Y′, Z, and Z′ are individually selected from —CH2, —NH2, of N-oxide;
- R1 is selected from halogen, —OH, —O—R10, C1-C24 alkyl, C3-C24 alkenyl, C4-C24 dienyl, C6-C24 trienyl, C8-C24 tetraenyl, C6-C18 aryl, substituted C6-C18 aryl, C1-C14-alkoxy, carboxy, cyano, C1-C14 alkylthio, C1-C14 alkanoyloxy, C1-C14 alkylsulfonyl, C2-C14alkoxycarbonyl, C2-C14 alkanoylamino, —S—R10, —SO2—R10, —NHSO2R10, and —NHCO2R10;
- R2 is selected from hydrogen, halogen, —OH, —O—R10, C1-C24 alkyl, C3-C24 alkenyl, C4-C24 dienyl, C6-C24 trienyl, C8-C24 tetraenyl, substituted C6-C18 aryl, wherein the substituted C6-C18 aryl is not substituted with halogen, C1-C14-alkoxy, carboxy, cyano, C1-C14 alkylthio, C1-C14 alkanoyloxy, C1-C14 alkylsulfonyl, C2-C14alkoxycarbonyl, C2-C14 alkanoylamino, —S—R10, —SO2—R10, —NHSO2R10, and —NHCO2R10;
- R3-R9 are independently selected from hydrogen, halogen, —OH, —O—R10, C1-C24 alkyl, C3-C24 alkenyl, C4-C24 dienyl, C6-C24 trienyl, C8-C24 tetraenyl, C6-C18 aryl, substituted C6-C18 aryl, C1-C14-alkoxy, carboxy, cyano, C1-C14 alkanoyloxy, C1-C14 alkylthio, C1-C14 alkylsulfonyl, C2-C14 alkoxycarbonyl, C2-C14 alkanoylamino, —S—R10, —SO2—R10, —NHSO2R10, and —NHCO2R10;
- and,
- R10 is phenyl or naphthyl, optionally substituted with one to three groups selected from C1-C6 alkyl, C6-C10 aryl, C1-C6 alkoxy, halogen, and C4-C20 hydroxyheteroaryl, wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen, and oxygen;
- or
- pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
A compound having the structure selected from:
- wherein:
- n=0-5;
- A, B, M, and D are individually selected from —CH2, —NH2, or N-oxide;
- R1, R8, R9, R11, R12, R13 are independently selected from hydrogen, halogen, —OH, —O—R14, C1-C24 alkyl, C3-C24 alkenyl, C4-C24 dienyl, C6-C24 trienyl, C8-C24 tetraenyl, C6-C18 aryl, substituted C6-C18 aryl, C1-C14-alkoxy, carboxy, cyano, C1-C14 alkanoyloxy, C1-C14 alkylthio, C1-C14 alkylsulfonyl, C2-C14 alkoxycarbonyl, C2-C14 alkanoylamino, —S—R14, —SO2—R14, —NHSO2R14, and —NHCO2R14;
- R2 is independently selected from hydrogen, halogen, —OH, —O—R14, C1-C24 alkyl, C3-C24 alkenyl, C4-C24 dienyl, C6-C24 trienyl, C8-C24 tetraenyl, C7-C18 aryl, substituted C6-C18 aryl, C1-C14-alkoxy, carboxy, cyano, C1-C14 alkanoyloxy, C1-C14 alkylthio, C1-C14 alkylsulfonyl, C2-C14 alkoxycarbonyl, C2-C14 alkanoylamino, —S—R14, —SO2—R14, —NHSO2R14, and —NHCO2R14;
- and,
- R14 is phenyl or naphthyl substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl, C1-C6 alkoxy, halogen, and C4-C20 hydroxyheteroaryl, wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen, and oxygen;
- or
- pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
A method of inhibiting Ral-GTPase protein binding activity, comprising contacting a Ral protein with a compound that blocks the conformational changes of a Ral protein associated with the GTP bound state.
A method of treating a cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound that inhibits the binding of a Ral protein with at least one protein selected from exo84, sec5, RalBP1, filamin A, PLD1, and ZONAB.
Dependencies are inferred from the claim text.