Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
Provided herein are methods, kits, and pharmaceutical compositions that include a PI3 kinase inhibitor for treating lupus, a fibrotic condition, or inflammatory myopathies and other conditions (e.g., skin conditions).
1. A method for reducing a lupus-associated symptom in a subject, comprising administering to the subject a phosphoinositide 3-kinase (PI3K) inhibitor, in an amount sufficient to decrease one or more symptoms, wherein the symptom comprises one or more of an elevated level of IFN-α, TNF-α, IL-6, IL-8, or IL-1.
2. The method of claim 1 , wherein the symptom comprises an elevated level of an anti-dsDNA autoantibody.
3. The method of claim 1 , wherein the symptom is chosen from one or more of nephritis, proteinuria, or spleen inflammation.
4. The method of claim 1 , wherein the symptom comprises an increased level of immune complexes.
5. The method of claim 1 , wherein the symptom comprises a vascular lesion.
6. The method of claim 1 , wherein the symptom comprises a cutaneous manifestation of lupus.
7. The method of claim 1 , wherein the symptom affects one or more of the skin, kidney, heart, lung, blood, or nervous system.
8. The method of claim 1 , wherein the PI3K inhibitor is a compound of Formula I-1:
or a pharmaceutically acceptable salt thereof, wherein
B is a moiety of Formula II:
wherein W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and
q is an integer of 0, 1, 2, 3, or 4;
X is a bond or —(CH(R 9 )) z —, and z is an integer of 1;
Y is —N(R 9 )—;
W d is:
R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro;
R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido, halo, cyano, hydroxy or nitro; and
each instance of R 9 is independently hydrogen, alkyl, or heterocycloalkyl.
9. The method of claim 8 , wherein B is a moiety of Formula II:
wherein W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
q is an integer of 0 or 1;
R 1 is hydrogen, alkyl, or halo;
R 2 is alkyl or halo; and
R 3 is hydrogen, alkyl, or halo.
10. The method of claim 8 , wherein X is —(CH(R 9 )) z —, and Y is —NH—.
11. The method of claim 8 , wherein R 3 is —H, —CH 3 , —CH 2 CH 3 , —CF 3 , —Cl or —F.
12. The method of claim 9 , wherein X is —(CH(R 9 )) z —, wherein R 9 is methyl and z=1; and
W d is
13. The method of claim 8 , wherein the compound is predominately in an (S)-stereochemical configuration.
14. The method of claim 8 , wherein the compound has a structure of Formula V-A2:
15. The method of claim 1 , wherein the PI3K inhibitor is a compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the PI3K inhibitor is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the PI3K inhibitor is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the PI3K inhibitor is a compound of the following structure:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the lupus is selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), drug-induced lupus, and neonatal lupus.
20. The method of claim 19 , wherein the lupus is SLE.
21. The method of claim 19 , wherein the CLE is acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), intermittent cutaneous lupus erythematosus, or chronic cutaneous lupus.
22. A method of treating lupus, comprising administering a PI3K inhibitor to a subject in need thereof, in an amount sufficient to treat the lupus in the subject, wherein the PI3K inhibitor is
or a pharmaceutically acceptable salt thereof, and wherein the treatment results in reduction of levels of one or more of IFN-α, TNF-α, IL-6, IL-8, IL-1, or an anti-dsDNA autoantibody in the subject.
23. A method of treating lupus comprising administering a PIK3 inhibitor to a subject in need thereof, in an amount sufficient to decrease or inhibit the lupus in the subject, wherein the treatment results in reduction of levels of one or more of IFN-α, TNF-α, IL-6, IL-8, or IL-1 in the subject.
24. The method of claim 23 , wherein the subject is a mammal.
25. The method of claim 24 , wherein the subject is a human.
26. The method of claim 23 , wherein the subject is a female.
27. The method of claim 23 , wherein the treatment results in reduction of a level of an anti-dsDNA autoantibody in the subject.
28. The method of claim 23 , wherein the treatment results in reduction of one or more of nephritis, proteinuria, or spleen inflammation in the subject.
29. The method of claim 23 , wherein the treatment results in reduction of levels of immune complexes in the subject.
30. The method of claim 23 , wherein the lupus is selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), drug-induced lupus, and neonatal lupus.
31. The method of claim 30 , wherein the lupus is SLE.
32. The method of claim 30 , wherein the CLE is acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), intermittent cutaneous lupus erythematosus, or chronic cutaneous lupus.
33. The method of claim 23 , further comprising administration of an additional therapeutic agent.
34. The method of claim 33 , wherein the additional therapeutic agent is chosen from one or more of belimumab, AGS-009, rontalizumab, vitamin D3, sifalimumab, AMG 811, IFNα Kinoid, CEP33457, epratuzumab, LY2127399, Ocrelizumab, Atacicept, A-623, SBI-087, AMG557, laquinimod, rapamycin, cyclophosphamide, azathioprine, mycophenolate, leflunomide, methotrexate, CNTO 136, tamibarotene, N-acetylcysteine, CDP7657, hydroxychloroquine, rituximab, carfilzomib, bortezomib, ONX 0914, IMO-3100, or DV 1179.
35. The method of claim 23 , wherein the PI3K inhibitor is a compound of Formula I-1:
or a pharmaceutically acceptable salt thereof, wherein
B is a moiety of Formula II:
wherein W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and
q is an integer of 0, 1, 2, 3, or 4;
X is a bond or —(CH(R 9 )) z —, and z is an integer of 1;
Y is —N(R 9 )—;
W d is:
R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro;
R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido, halo, cyano, hydroxy or nitro; and
each instance of R 9 is independently hydrogen, alkyl, or heterocycloalkyl.
36. The method of claim 35 , wherein B is a moiety of Formula II:
wherein W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
q is an integer of 0 or 1;
R 1 is hydrogen, alkyl, or halo;
R 2 is alkyl or halo; and
R 3 is hydrogen, alkyl, or halo.
37. The method of claim 35 , wherein X is —(CH(R 9 )) z —, and Y is —NH—.
38. The method of claim 35 , wherein R 3 is —H, —CH 3 , —CH 2 CH 3 , —CF 3 , —Cl or —F.
39. The method of claim 36 , wherein X is —(CH(R 9 )) z —, wherein R 9 is methyl and z=1; and
W d is
40. The method of claim 35 , wherein the compound is predominately in an (S)-stereochemical configuration.
41. The method of claim 35 , wherein the compound has a structure of Formula V-A2:
42. The method of claim 23 , wherein the PI3K inhibitor is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
43. The method of claim 23 , wherein the PI3K inhibitor is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
44. The method of claim 23 , wherein the PI3K inhibitor is a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
45. The method of claim 23 , wherein the PI3K inhibitor is a compound of the following structure:
or a pharmaceutically acceptable salt thereof.
46. The method of claim 1 , wherein the PI3K inhibitor is a compound of the following structure:
or a pharmaceutically acceptable salt thereof.
47. The method of claim 23 , wherein the PI3K inhibitor is a compound of the following structure:
or a pharmaceutically acceptable salt thereof.
48. The method of claim 1 , wherein the symptom is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% relative to a control level.