Death receptor sensitizing compounds and methods of use therefor
AssigneeBurnham Institute for Medical Research
InventorsAaron D Schimmer, John C. Reed
Life of this patent
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Abstract
Methods of identifying death receptor sensitizing compounds and methods of using death receptor sensitizing compounds are provided.
Claims20
A method to enhance TNF-family death receptor ligand-mediated killing of tumor cells in a mammal, comprising administering to a mammal having TNF-family death receptor ligand-resistant cancer an effective amount of a compound of formula (I):
- wherein,
- R1 is alkylene, alkenylene, arylene, heteroarylene, heterocyclene or cycloalkylene;
- Ra is F, Cl, Br or I;
- R9 is O or NRx;
- each Rzz is independently O, NRx or S;
- R10 is alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocycle, cycloalkyl, amino, alkylamino, NRxRy or COORx;
- and
- each Rx and Ry is independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl;
- or a pharmaceutically acceptable salt thereof.
A method to inhibit TNF-family death receptor ligand-resistant cancer in a mammal, comprising identifying a mammal having TNF-family death receptor ligand-resistant cancer;
- and administering to the mammal an effective amount of a compound of formula (I):
- wherein,
- R1 is alkylene, alkenylene, arylene, heteroarylene, heterocyclene or cycloalkylene;
- Ra is F, Cl, Br or I;
- R9 is O or NRx;
- each Rzz is independently O, NRx or S;
- R10 is alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocycle, cycloalkyl, amino, alkylamino, NRx Ry or COORx;
- and
- each Rx and Ry is independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl;
- or a pharmaceutically acceptable salt thereof.
A method to sensitize prostate cancer, breast cancer or ovarian cancer cells that are resistant to TNF-family death receptor ligand-mediated killing comprising contacting the cells with an effective amount of a compound of formula (I):
- wherein,
- R1 is alkylene, alkenylene, arylene, heteroarylene, heterocyclene or cycloalkylene;
- Ra is F, Cl, Br or I;
- R9 is O or NRx;
- each Rzz is independently O, NRx or S;
- R10 is alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocycle, cycloalkyl, amino, alkylamino, NRxRy or COORx;
- and
- each Rx and Ry is independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl;
- or a pharmaceutically acceptable salt thereof.
A method to inhibit metastases comprising administering to a mammal having TNF-family death receptor ligand-resistant cancer an effective amount of a compound of formula (I):
- wherein,
- R1 is alkylene, alkenylene, arylene, heteroarylene, heterocyclene or cycloalkylene;
- Ra is F, Cl, Br or I;
- R9 is O or NRx;
- each Rzz is independently O, NRx or S;
- R10 is alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocycle, cycloalkyl, amino, alkylamino, NRxRy or COORx;
- and
- each Rx and Ry is independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl;
- or a pharmaceutically acceptable salt thereof.
A method to sensitize cells to anoikis, comprising administering to a mammal having TNF-family death receptor ligand-resistant cancer an effective amount of a compound of formula (I):
- wherein,
- R1 is alkylene, alkenylene, arylene, heteroarylene, heterocyclene or cycloalkylene;
- Ra is F, Cl, Br or I;
- R9 is O or NRx;
- each Rzz is independently O, NRx or S;
- R10 is alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, heteroaryl, heterocycle, cycloalkyl, amino, alkylamino, NRxRy or COORx;
- and
- each Rx and Ry is independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.