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1. (WO2018226721) COMPOSITIONS AND METHODS FOR REACTIVATING LATENT IMMUNODEFICIENCY VIRUS USING A GSK-3 INHIBITOR
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CLAIMS

What is claimed is:

1. A method of reactivating a latent human immunodeficiency virus (HIV) integrated into the genome of a cell infected with HIV, the method comprising contacting the cell with a glycogen synthase kinase 3 inhibitor, wherein the glycogen synthase kinase 3 inhibitor reactivates the latent HIV integrated into the genome of the cell.

2. The method of claim 1, wherein the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase 3 a inhibitor.

3. The method of claim 1, wherein the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase 3β inhibitor.

4. The method of claim 1, wherein the glycogen synthase kinase 3 inhibitor is an inhibitor of both glycogen synthase kinase 3a and glycogen synthase kinase 3β.

5. The method of any one of claims 1-4, wherein the contacting does not significantly reduce CD4+ T cell viability.

6. The method of any one of claims 1-5, wherein the contacting does not significantly reduce CD8+ T cell viability.

7. The method of any one of claims 1-6, wherein the contacting does not significantly reduce NK cell viability.

8. The method of any one of claims 1-7, wherein the contacting does not significantly increase CD4+ T cell activation.

9. The method of any one of claims 1-8, wherein the contacting does not significantly inhibit or enhances cytoxic effector functions of CTLs or NK cells.

10. The method of any one of claims 1-9, wherein the glycogen synthase kinase 3 inhibitor is:

a) a compound of Formula I:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

n is an integer from 1 to 8;

each of R1, R2, R3, R4, R5, R6, Ra and Rb are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR7R8, -NR7C(0)R8, -N=CR7R8,

wherein t is 0, 1, 2 or 3; and

each of R7 and R8 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy or halogen; or b) a compound of Formula II:


(Formula II)

or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R1 and R2 are independently C5-C12 cycloalkyl, substituted C5-C12 cycloalkyl, C5-C12 heterocycloalkyl, substituted C5-C12 heterocycloalkyl, C5-C12 aryl, substituted C5-C12 aryl, C5-C12 heteroaryl, substituted C5-C12 heteroaryl,

wherein the compound of Formula I or the compound ol Formula 11 reactivates the latent HIV integrated into the genome of the cell.

1 1. The method of claim 10, wherein the compound of Formula II is a compound of Formula Ila:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R2 are independently C5-C12 cycloalkyl, substituted C5-C12 cycloalkyl, C5-C12 heterocycloalkyl, substituted C5-C12 heterocycloalkyl, C5-C12 aryl, substituted C5-C12 aryl, C5-C12 heteroaryl, substituted C5-C12 heteroaryl;

each of R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR R8, -NR7C(0)R8, -N=CR7R8, wherein t is 0, 1 , 2 or 3,

12. The method of claim 10, wherein the compound of Formula II is a compound of Formula lib:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

each of R3, R4, R5, R6, R7, R8, R9, R10, R11, R" and iJ are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,

heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR7R8, - R7C(0)R8, - N=CR7RS, wherein t is 0, 1, 2 or 3.

13. The method of any one of claims 1-9, wherein the glycogen synthase kinase 3 inhibitor is Tideglusib (4-benzyl-2-(naphthalen-l-yl)-l,2,4-thiadiazolidine-3,5-dione)) or pharmaceutically acceptable salt or derivative thereof or SB-216763 (3-(2,4-Dichlorophenyl)-4-(l -methyl- lH-indol-3-yl)-lH-pyrrole-2,5-di one) or pharmaceutically acceptable salt or derivative thereof.

14. The method of any one of claims 1-13, wherein the contacting occurs in lymphoid tissue.

15. A method of reducing the number of cells containing a latent human immunodeficiency virus in an individual, the method comprising administering to the individual an effective amount of a glycogen synthase kinase 3 inhibitor, wherein the glycogen synthase kinase 3 inhibitor reactivates latent HIV integrated into the genome of one or more cells in the individual.

16. The method of claim 15, wherein the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase 3 a inhibitor.

17. The method of claim 15, wherein the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase 3β inhibitor.

18. The method of claim 15, wherein the glycogen synthase kinase 3 inhibitor is an inhibitor of both glycogen synthase kinase 3a and glycogen synthase kinase 3β.

19 The method of any one of claims 15-18, wherein the administering does not significantly reduce CD4+ T cell viability in the individual.

20. The method of any one of claims 15-19, wherein the administering does not significantly reduce CD8+ T cell viability in the individual.

21. The method of any one of claims 15-20, wherein the administering does not significantly reduce NK cell viability in the individual.

22. The method of any one of claims 15-21, wherein the administering does not significantly increase CD4+ T cell activation in the individual.

23. The method of any one of claims 15-22, wherein the administering does not significantly inhibit or enhances cytoxic effector functions of CTLs or NK cells in the individual.

24. The method of any one of claims 15-23, wherein the glycogen synthase kinase 3 inhibitor is:

a) a compound of Formula I:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

n is an integer from 1 to 8;

each of R1, R2, R3, R4, R5, R6, Ra and R are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -0C(O)R , -S(0)t-R , -ΝΚ Γ, -NR7C(0)R8, -N=CR7R8,

wherein t is 0, 1, 2 or 3; and

each of R7 and R8 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy or halogen; or b) a compound of Formula II:


(Formula II)

or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R1 and R2 are independently C5-C12 cycloalkyl, substituted C5-C12 cycloalkyl, C5-C12 heterocycloalkyl, substituted C5-C12 heterocycloalkyl, C5-C12 aryl, substituted C5-C12 aryl, C5-C12 heteroaryl, substituted C5-C12 heteroaryl.

25. The method of claim 24, wherein the compound of Formula II is a compound of Formula Ila:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R2 are independently C5-C12 cycloalkyl, substituted C5-C12 cycloalkyl, C5-C12 heterocycloalkyl, substituted C5-C12 heterocycloalkyl, C5-C12 aryl, substituted C5-C12 aryl, C5-C12 heteroaryl, substituted C5-C12 heteroaryl;

each of R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -

C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R , -JNK'K", -JNK'C(U)R", -N=CR7R8, wherein t is 0, 1, 2 or 3,

26. The method of claim 24, wherein the compound of Formula II is a compound of Formula lib:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

each of R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,

heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR7R8, - R7C(0)R8, - N=CR7R8, wherein t is 0, 1, 2 or 3.

27. The method of any one of claims 15-23, wherein the glycogen synthase kinase 3 inhibitor is Tideglusib (4-benzyl-2-(naphthalen-l-yl)-l,2,4-thiadiazolidine-3,5-dione)) or pharmaceutically acceptable salt or derivative thereof or SB-216763 (3 -(2,4-Dichlorophenyl)-4-(l -methyl- lH-indol-3-yl)-lH-pyrrole-2,5-di one) or pharmaceutically acceptable salt or derivative thereof.

28. The method of any one of claims 15-27, wherein said administering is effective to reduce the number of cells containing a latent human immunodeficiency virus in the individual by at least 20%.

29. A method of treating a human immunodeficiency virus (HIV) infection in an individual, the method comprising:

administering to an individual an effective amount of a glycogen synthase kinase 3 inhibitor, wherein the glycogen synthase kinase 3 inhibitor reactivates latent HIV integrated into the genome of a cell in the individual; and

administering to the individual an effective amount of a second active agent, wherein the second active agent inhibits an immunodeficiency virus function selected from viral replication, viral protease activity, viral reverse transcriptase activity, viral entry into a cell, viral integrase activity, viral Rev activity, viral Tat activity, viral Nef activity, viral Vpr activity, viral Vpu activity, and viral Vif activity.

30. The method of claim 29, wherein the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase 3 a inhibitor.

31. The method of claim 29, wherein the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase 3β inhibitor.

32. The method of claim 29, wherein the glycogen synthase kinase 3 inhibitor is an inhibitor of both glycogen synthase kinase 3a and glycogen synthase kinase 3β.

33. The method of any one of claims 29-32, wherein the administering does not significantly reduce CD4+ T cell viability in the individual.

34. The method of any one of claims 29-33, wherein the administering does not significantly reduce CD8+ T cell viability in the individual

35. The method of any one of claims 29-34, wherein the administering does not significantly reduce NK cell viability in the individual.

36. The method of any one of claims 29-35, wherein the administering does not significantly increase CD4+ T cell activation in the individual

37. The method of any one of claims 29-36, wherein the administering does not significantly inhibit or enhances cytoxic effector functions of CTLs or NK cells in the individual.

38. The method of any one of claims 29-37, wherein the glycogen synthase kinase 3 inhibitor is:

a) a compound of Formula I:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

n is an integer from 1 to 8;

each of R1, R2, R3, R4, R5, R6, Ra and Rb are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR7R8, -NR7C(0)R8, -N=CR7R8,

wherein t is 0, 1, 2 or 3; and

each of R7 and R8 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy or halogen; or b) a compound of Formula II:


(Formula II)

or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R1 and R2 are independently C5-C12 cycloalkyl, substituted C5-C12 cycloalkyl, C5-C12 heterocycloalkyl, substituted C5-C12 heterocycloalkyl, C5-C12 aryl, substituted C5-C12 aryl, C5-C12 heteroaryl, substituted C5-C12 heteroaryl.

I l l

The method of claim 38, wherein the compound of Formula II is a compound of Formula Ila:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

R2 are independently C5-C12 cycloalkyl, substituted C5-C12 cycloalkyl, C5-C12 heterocycloalkyl, substituted C5-C12 heterocycloalkyl, C5-C12 aryl, substituted C5-C12 aryl, C5-C12 heteroaryl, substituted C5-C12 heteroaryl;

each of R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR7R8, -NR7C(0)R8, -N=CR7R8, wherein t is 0, 1, 2 or 3,

40. The method of claim 38, wherein the compound of Formula II is a compound of Formula lib:


or a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein:

each of R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,

heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl,

hydroxyl, alkoxyl, substituted alkoxyl, substituted acyloxy, alkoxycarbonyl, substituted alkoxycarbonyl, thiol, acyl, amino, substituted amino, aminoacyl, acylamino, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, -COR7, -C(0)OR7, -C(0)NR7R8, -C=NR7, -OR7, -OC(0)R7, -S(0)t-R7, -NR7R8, -NR7C(0)R8, - N=CR7RS, wherein t is 0, 1, 2 or 3.

41. The method of any one of claims 29-37, wherein the glycogen synthase kinase 3 inhibitor is Tideglusib (4-benzyl-2-(naphthalen-l-yl)-l,2,4-thiadiazolidine-3,5-dione)) or pharmaceutically acceptable salt or derivative thereof or SB-216763 (3 -(2,4-Dichlorophenyl)-4-(l -methyl- lH-indol-3-yl)-lH-pyrrole-2,5-di one) or pharmaceutically acceptable salt or derivative thereof.

42. The method of any one of claims 29-41, wherein one or both of said administering steps is by a vaginal route of administration, by a rectal route of

administration, by an oral route of administration, or by an intravenous route of

administration.