Methods and Compositions for Modulating AKT3

Patent metadata

Field	Value
Publication number	US-2020390884-A1
Application number	US-202016989481-A
Country	US
Kind code	A1
Filing date	Aug 10, 2020
Priority date	Jan 15, 2016
Publication date	Dec 17, 2020
Grant date	—

Abstract

Compounds and compositions for selectively modulating Akt3 are provided. Methods of using the compounds are also provided. Because Akt3 modulates the suppressive function of natural Tregs and the polarization of induced Tregs, the disclosed compounds are useful for modulating immune responses.

First claim

We claim:

1 . A compound selected from the group consisting of

or an enantiomer, polymorph, or pharmaceutically acceptable salt thereof.

2 . A pharmaceutical composition comprising one or more of the compounds of claim 1 .

3 . A method of modulating an immune suppressive response in a subject in need thereof comprising administering to the subject a composition comprising one or more compounds according to claim 1 that selectively modulates Akt3 by an amount effective to modulate the immune suppressive response in the subject.

4 . The method of claim 3 , wherein the subject has an autoimmune disease, obesity, transplant rejection, Graft versus Host disease, an inflammatory disorder, cancer, or an infection.

5 . The method of claim 4 , wherein the cancer is selected from the group consisting of bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, uterine, ovarian, testicular and hematologic cancers.

6 . The method of claim 4 , wherein the autoimmune disease is selected from the group consisting of achalasia, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Baló disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, Eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, myositis, narcolepsy, neonatal Lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm & testicular autoimmunity, Stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis/Giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, Type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada Disease.

7 . The method of claim 3 , wherein the immune suppressive response that is modulated is selected from the group consisting of an immune suppressive function of natural Treg (nTreg) and induction of conventional T cells into induced Treg (iTreg).

8 . The method of claim 7 , wherein the immune suppressive function of nTreg is the secretion of one or more anti-inflammatory cytokines.

9 . The method of claim 8 wherein the anti-inflammatory cytokine is IL10, TGFβ, or a combination thereof.

12 . The method of claim 3 , wherein the one or more compounds according to claim 1 inhibit Akt3.

13 . The method of claim 3 , wherein the one or more compounds according to claim 1 activate Akt3.

14 . The method of claim 3 further comprising administering to the subject a second active agent.

15 . A method of modulating an immune response in a subject in need thereof comprising administering to the subject a population of immune cells contacted ex vivo with one or more of the compounds according to claim 1 in an amount effective to modulate the immune cells.

16 . The method of claim 15 , wherein the immune cells are regulatory T cells.

17 . The method of claim 15 , wherein the immune cells are activated by the compound.

18 . The method of claim 15 , wherein the immune cells are inhibited by the compound.

19 . The method of claim 15 , wherein the subject in need thereof has an autoimmune disease, obesity, transplant rejection, Graft versus Host disease, an inflammatory disorder, cancer, or an infection.

Assignees

• Univ Res Inst Inc Augusta

Inventors

• Khleif Samir N
• Mkrtichyan Mikayel
• Lebedyeva Iryna
• Albers Thomas

Classifications

• A61K2039/5158

  Antigen-pulsed cells, e.g. T-cells · CPC title

• A61K39/0011

  Cancer antigens · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title