Small molecule bcl-2 functional converters as cancer therapeutics
AssigneeOregon State University
InventorsSiva K. Kolluri, Prasad R. Kopparapu, Martin Pearce
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Abstract
Methods for inducing growth inhibition or apoptosis of Bcl-2-expressing cells and treatments of Bcl-2 expressing cancers are provided. Additionally, assays for agents that can induce apoptosis of Bcl-2 expressing cells are disclosed.
Claims20
A method for inducing growth inhibition or apoptosis of a Bcl-2-expressing cell, comprising contacting a Bcl-2-expressing cell with an agent that exposes the BH3 domain of Bcl-2 thereby converting Bcl-2 into a pro-apoptotic protein and activating the intrinsic apoptosis pathway,
- wherein the agent is a compound of formula (IV):
- or a stereoisomer, tautomer, hydrate, or salt thereof,
- wherein:
- R1 is H, C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl;
- R2 is H, C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl;
- R10 is H or R10 and R2, taken together, form an oxo group (═O);
- R3, R4, R5, and R6 are independently H, halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8alkynyl, or R5 and R6, together with the carbon atoms to which each is attached, form a 5 or 6-membered aromatic or heteroaromatic ring;
- R9 is H or R9 and R1 form a C1-C3 alkylene;
- Y is NH2 or OH;
- X is N or C;
- and
- Z is OH, NH2, OR8, or
- wherein R8 is H or C1-C8 alkyl. n is 1 or 2, and R7 is H, OH, NH2, or C1-C8 alkyl.
A method of treating Bcl-2-expressing cancer in a subject, comprising administering to the subject in need of cancer treatment, a therapeutically effective amount of a compound of formula (IV):
- or a stereoisomer, tautomer, hydrate, or salt thereof,
- wherein:
- R1 is H, C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl;
- R2 is H, C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl;
- R10 is H or R10 and R2, taken together, form an oxo group (═O);
- R3, R4, R5, and R6 are independently H, halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, or R5 and R6, together with the carbon atoms to which each is attached, form a 5 or 6-membered aromatic or heteroaromatic ring;
- R9 is H or R9 and R1 form a C1-C3 alkylene;
- Y is NH2 or OH;
- X is N or C;
- and
- Z is OH, NH2, OR8, or
- wherein R8 is H or C1-C8 alkyl, n is 1 or 2, and R7 is H, OH, NH2, or C1-C8 alkyl.
A method of treating Bcl-2-expressing cancer, comprising targeting the Bcl-2 protein in a cancer cell of a subject, by administering to the subject in need of cancer treatment, a therapeutically effective amount of a compound of formula (IV):
- or a stereoisomer, tautomer, hydrate, or salt thereof,
- wherein:
- R1 is H, C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl;
- R2 is H, C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl;
- R10 is H or R10 and R2, taken together, form an oxo group (═O);
- R3, R4, R5, and R6 are independently H, halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, or R5 and R6, together with the carbon atoms to which each is attached, form a 5 or 6-membered aromatic or heteroaromatic ring;
- R9 is H or R9 and R1 form a C1-C3 alkylene;
- Y is NH2 or OH;
- X is N or C;
- and
- Z is OH, NH2, OR8, or
- wherein R8 is H or C1-C8 alkyl, n is 1 or 2, and R7 is H, OH, NH2, or C1-C8 alkyl.
Dependencies are inferred from the claim text.