# US 2020/0390884 A1 · Methods and Compositions for Modulating AKT3

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- Number: US 2020/0390884 A1
- Document ID: US20200390884A1
- Status: Published application
- Kind: A1
- Application number: 16/989,481
- Filed: 2020-08-10
- Published: 2020-12-17
- Earliest claimed: 2016-01-15
- Assignees: Augusta University Research Institute, Inc.
- Applicants: Augusta University Research Institute, Inc.
- Inventors: Samir N. KHLEIF; Mikayel MKRTICHYAN; Iryna LEBEDYEVA; Thomas ALBERS
- Web page: https://patentgrep.com/patent/US20200390884A1

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/0011: {Cancer antigens}
- A61P 35/00: Antineoplastic agents
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- A61K 2039/5158: {Antigen-pulsed cells, e.g. T-cells}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/57: {characterised by the type of response, e.g. Th1, Th2}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A compound selected from the group consisting of
or an enantiomer, polymorph, or pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 3)

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.

### Claim 5 (depends on 4)

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.

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 3)

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).

### Claim 8 (depends on 7)

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

### Claim 9 (depends on 8)

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

### Claim 12 (depends on 1, 3)

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

### Claim 13 (depends on 1, 3)

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

### Claim 14 (depends on 3)

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

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 15)

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

### Claim 17 (depends on 15)

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

### Claim 18 (depends on 15)

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

### Claim 19 (depends on 15)

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.