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US 11,229,641 B2Granted
Inhibitors of Bcl-2
AssigneeCase Western Reserve University
InventorClark Distelhorst
Life of this patent
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Abstract
Compounds and pharmaceutical compositions thereof for inducing apoptosis in a cell expressing Bcl-2 and IP3R and their use in a method for treating neoplastic disorders in a subject.
Claims20
A method of inducing apoptosis in a cell expressing Bcl-2 and IP3R, comprising:
- administering to the cell a therapeutically effective amount of a compound that inhibits binding of Bcl-2 to IP3 receptors (IP3R) of cells that express IP3R and Bcl-2, wherein the compound is derived from the Bcl-2 binding domain of IP3R;
- wherein the compound has the general formula (I):
- wherein X1 is CH2, or C═O;
- R1, R2, R3, R4, and R5 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, C2-C24 alkylcarbonyl, C6-C20 arylcarbonyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof;
- and pharmaceutically acceptable salts thereof.
2 more elements
A method of treating a neoplastic disorder in a subject, comprising:
- administering to a subject's neoplastic cells expressing IP3R and Bcl-2 a therapeutically effective amount of a compound that inhibits binding of Bcl-2 to IP3 receptors (IP3R), wherein the compound is derived from the Bcl-2 binding domain of IP3R;
- wherein the neoplastic disorder comprises a Bcl-2 associated cancer selected from the group consisting of small cell lung cancer, chronic lymphocytic leukemia (CLL), follicular lymphoma, diffuse large B-cell lymphoma, and multiple myeloma (MM);
- the compound having the general formula (I):
- wherein X1 is CH2, or C═O;
- R1, R2, R3, R4, and R5 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, C2-C24 alkylcarbonyl, C6-C20 arylcarbonyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof;
- and pharmaceutically acceptable salts thereof.
3 more elements
Dependencies are inferred from the claim text.