Compositions and methods for modulating apoptosis in cells over-expressing Bcl-2 family member proteins
AssigneeFred Hutchinson Cancer Research Center
InventorsDavid M. Hockenberry, Julian A. Simon, Shie-Pon Tzung
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Abstract
The present invention provides agents and compositions for modulating the apoptotic state of a cell. The agents comprise derivatives of antimycins which bind to an anti-apoptotic Bcl-2 family member protein. Further, the agents preferentially induce apoptosis in cells that over-express anti-apoptotic Bcl-2 family member proteins and typically exhibit reduced binding affinity for cytochrome B. Pharmaceutical uses of the agents and compositions include treating apoptosis-associated disease, such as neoplasia and drug resistance, are also disclosed.
Claims8
An apoptotic composition that induces apoptosis by binding to a Bcl-2 family member protein and preferentially inducing apoptosis in a cell that over-expresses the Bcl-2 family member protein, the composition having the following formula II,
- having an absolute configuration of [2R, 3R, 4S, 7S, 8R], and wherein
- R1 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- R2 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- R3 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- R4 is hydrogen, a C1–C8 linear or branched alkane, a C1–C8 hydroxyalkane, or a substituted alkyl group;
- R5 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C3–C8 di- or tri-alkylamine, a C1–C8 carboxylic acid, a C2–C8 amide, or a substituted alkyl group;
- and
- R6 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group.
A method for treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a composition, wherein the composition comprises an antimycin of the following formula, and having an absolute configuration of [2R, 3R, 4S, 7S, 8R]:
- wherein R1 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- R2 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- R3 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- R4 is hydrogen a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane or a substituted alkyl group;
- R5 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-alkylamine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group;
- and
- R6 is hydrogen, a C1–C8 linear or branched alkane, hydroxyl, a C1–C8 hydroxyalkane, amino, a C1–C8 di- or tri-amine, a C1–C8 amide, a C1–C8 carboxylic acid, or a substituted alkyl group.
Dependencies are inferred from the claim text.