Proteasome inhibitors and uses thereof
The invention relates to methods and compositions for inhibiting proteasome activity using cinnamate compounds. These cinnamate compounds can be formulated for topical or systemic use for skin disorders such as psoriasis.
1. A method of treating a skin disorder associated with proteasome activity selected from the group consisting of angiosarcoma, hemangioendothelioma, basal cell carcinoma, squamous cell carcinoma, malignant melanoma and Kaposi's sarcoma, psoriasis, lymphangiogenesis, hemangioma of childhood, Sturge-Weber syndrome, verruca vulgaris, neurofibromatosis, tuberous sclerosis, pyogenic granulomas, recessive dystrophic epidermolysis bullosa, venous ulcers, acne, rosacea, eczema, molluscum contagious, seborrheic keratosis, and actinic keratosis, wherein the dihydrocinnamate compound interacts with a proteasome to inhibit proteasome activity, and wherein the inhibition of proteasome activity treats the disorder, comprising administering a topical pharmaceutical composition to a patient in need thereof comprising an effective amount of a dihydrocinnamate compound and a pharmaceutically-acceptable carrier, wherein the dihydrocinnamate compound inhibits proteasome activity, and wherein the dihydrocinnamate compound is
wherein W is selected from the group consisting of an alkyl group, a methylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and wherein X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, such that OR is a dihydrocinnamate moiety, and wherein at least one of X 1 to X 5 is said OR group;
wherein W and XI-X4 are as defined above,
or
(iii) a dihydrocinnamate compound selected from the group consisting of
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the dihydrocinnamate moiety in the listed compounds can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
2. The method of claim 1 , wherein the dihydrocinnamate compound inhibits a chymotrypsin-like activity of the proteasome.
3. The method of claim 1 , wherein the dihydrocinnamate compound is selected from the group consisting of
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the dihydrocinnamate moiety in the listed compounds can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
4. The method of claim 1 , wherein the dihydrocinnamate compound is pentraerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate).
5. The method of claim 1 , wherein the dihydrocinnamate compound has the formula:
wherein W is selected from the group consisting of an alkylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and wherein X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, such that OR is a dihydrocinnamate moiety, and wherein at least one of X 1 to X 5 is said OR group,
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the moiety can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
6. The method of claim 1 , wherein the hydrocinnamate compound has the formula:
wherein W is selected from the group consisting of an alkylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and wherein X 1 to X 4 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, such that OR is a dihydrocinnamate moiety, wherein at least one of X 1 to X 4 is said OR group,
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the —C(O)—CH 2 CH 2 -phenyl moiety can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido,
and a pharmaceutically-acceptable carrier, wherein the cinnamate compound inhibits proteasome activity.
7. A method of treating a skin disorder associated with proteasome activity selected from the group consisting of lupus, arthritis, and multiple sclerosis, wherein the dihydrocinnamate compound interacts with a proteasome to inhibit proteasome activity, and wherein the inhibition of proteasome activity treats the disorder, comprising administering a topical pharmaceutical composition to a patient in need thereof comprising an effective amount of a dihydrocinnamate compound and a pharmaceutically-acceptable carrier, wherein the dihydrocinnamate compound inhibits proteasome activity, and wherein the dihydrocinnamate compound is
wherein W is selected from the group consisting of an alkyl group, a methylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and
wherein X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, such that OR is a dihydrocinnamate moiety, and wherein at least one of X 1 to X 5 is said OR group;
wherein W and XI-X4 are as defined above,
or
(iii) a dihydrocinnamate compound selected from the group consisting of
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the dihydrocinnamate moiety in the listed compounds can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
8. The method of claim 7 , wherein the dihydrocinnamate compound in the composition of claim 1 is pentraerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate).
9. The method of claim 1 , wherein the dihydrocinnamate compound inhibits a chymotrypsin-like activity of the proteasome.
10. The method of claim 7 , wherein the dihydrocinnamate compound is selected from the group consisting of
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the dihydrocinnamate moiety in the listed compounds can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
11. The method of claim 7 , wherein the dihydrocinnamate compound is pentraerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate).
12. The method of claim 7 , wherein the dihydrocinnamate compound has the formula:
wherein W is selected from the group consisting of an alkylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and wherein X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, and wherein at least one of X 1 to X 5 is said OR group,
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the hydrocinnamate moiety can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
13. The method of claim 7 , wherein the dihydrocinnamate compound has the formula:
wherein W is selected from the group consisting of a methyl group, an alkyl group, a methylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and wherein Xi to X 4 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, wherein at least one of X 1 to X 4 is said OR group,
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the hydrocinnamate moiety can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido,
wherein the hydrocinnamate compound interacts with a proteasome to inhibit proteasome activity, wherein the inhibition of proteasome activity treats the disorder.
14. The method of claim 1 , wherein the disorder is psoriasis.
15. The method of claim 1 , wherein the disorder is acne, actinic keratosis, or rosacea.
16. A method of treating a skin disorder associated with proteasome activity selected from the group consisting of bladder cancer, leukemias, lymphomas, sarcomas, and epithelial cancers, wherein the dihydrocinnamate compound interacts with a proteasome to inhibit proteasome activity, and wherein the inhibition of proteasome activity treats the disorder, comprising administering a topical pharmaceutical composition to a patient in need thereof comprising an effective amount of a dihydrocinnamate compound and a pharmaceutically-acceptable carrier, wherein the dihydrocinnamate compound inhibits proteasome activity, and wherein the dihydrocinnamate compound is
wherein W is selected from the group consisting of an alkyl group, a methylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom, and wherein X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is —C(O)—CH 2 CH 2 -phenyl, such that OR is a dihydrocinnamate moiety, and wherein at least one of X 1 to X 5 is said OR group;
wherein W and XI-X4 are as defined above,
or
(iii) a dihydrocinnamate compound selected from the group consisting of
and analogs thereof wherein one or more of the hydrogen atoms on the phenyl ring in the dihydrocinnamate moiety in the listed compounds can be replaced with a moiety selected from the group consisting of halogen, hydroxyl, ether, alkyl, aryl, nitro, cyano, thiol, thioester, amino, and amido.
17. The method of claim 16 , wherein the dihydrocinnamate compound is pentraerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate).