Small molecule Bcl-2 functional converters as cancer therapeutics
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.
1. 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 a therapeutically effective amount of a compound of formula (III):
or a tautomer, hydrate, or salt thereof,
wherein:
Ar 1 is optionally substituted C6-C10 aryl or optionally substituted C5-C10 heteroaryl;
R 1 and R 2 are independently H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, optionally substituted C1-C8 alkynyl, O (C1-C8 alkyl), or C (O) NHR, wherein R is optionally substituted C1-C8 alkyl, optionally substituted C6-C10 aryl, or optionally substituted C5-C10 heteroaryl; or together with the carbon atoms to which each is attached, R 1 and R 2 form an optionally substituted 6-membered cycle;
Y is COOH, CONH 2 , optionally substituted C6-C10 aryl, optionally substituted C5-C10 heteroaryl, or C (O) X; and
X is optionally substituted C6-C10 aryl, or optionally substituted C3-C10 heteroaryl.
2. The method of claim 1 , wherein the compound is selected from the group consisting of:
2-[(2-methoxy-5-nitrobenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-5,6-dimethyl-3-phenylthieno[2,3-d]pyrimidin-4 (3H)-one;
5,6-dimethyl-2-{[2-(4-nitrophenyl)-2-oxoethyl]thio}-3-phenylthieno[2,3-d]pyrimidin-4 (3H)-one;
2-{[2-oxo-2-(2-thienyl)ethyl]thio}-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-[(4-nitrobenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-(benzylthio)-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-[(4-methoxybenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
{[3-(4-ethoxyphenyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]-benzothieno[2,3-d]pyrimidin-2-yl]thio}acetic acid;
2-{[3-(4-ethoxyphenyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-2-yl]thio}acetamide;
4-({[3-(4-methoxyphenyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-2-yl]thio}methyl)benzoic acid; and
7-tert-butyl-2-[(4-methoxybenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
or a tautomer, hydrate, or salt thereof.
3. 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 2-[(2-methoxy-5-nitrobenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3 H)-one, 2-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-5,6-dimethyl-3-phenylthieno[2,3-d]pyrimidin-4 (3H)-one;
5,6-dimethyl-2-{[(2-methyl-1,3-thiazol-4-yl)methyl]thio}-3-phenylthieno[2,3-d]pyrimidin-4 (3H)-one;
5,6-dimethyl-2-{[2-(4-nitrophenyl)-2-oxoethyl]thio}-3-phenylthieno[2,3-d]pyrimidin-4 (3H)-one;
2-{[2-(4-fluorophenoxy)ethyl]thio}-5,6-dimethyl-3-phenylthieno[2,3-d]pyrimidin-4 (3H)-one;
2-{[2-oxo-2-(2-thienyl)ethyl]thio}-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-[(4-nitrobenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-(benzylthio)-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
2-[(4-methoxybenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one;
{[3-(4-ethoxyphenyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]-benzothieno[2,3-d]pyrimidin-2-yl]thio} acetic acid;
2-{[3-(4-ethoxyphenyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-2-yl]thio} acetamide;
4-({[3-(4-methoxyphenyl)-4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-2-yl]thio} methyl)benzoicacid; 7-tert-butyl-2-[(4-methoxybenzyl)thio]-3-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4 (3H)-one; or a tautomer, hydrate, or salt thereof.