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US-12616690-B2 - Specific AKT3 activator and uses thereof

US12616690B2US 12616690 B2US12616690 B2US 12616690B2US-12616690-B2

Abstract

Compositions and methods of selectively activating Akt3 are provided.

Inventors

  • Samir Khleif
  • Mikayel Mkrtichyan

Assignees

  • AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.

Dates

Publication Date
20260505
Application Date
20240315

Claims (20)

  1. 1 . A compound according to Formula I: or a pharmaceutically acceptable enantiomer, or salt thereof, wherein: rings A and C are independently phenyl, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, quinazoline, isoquinoline, naphthalene, naphthyridine, indole, isoindole, cinnoline, phthalazine, quinoxaline, pteridine, purine, or benzimidazole; ring B is a six-membered aryl, an N-containing heteroaryl mono- or bicyclic ring system containing one or more N atoms, or an aryl bicyclic ring system; R 1 is selected from the group consisting of —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, or —(C 3 -C 20 )-heteroaryl groups optionally substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen; X, Y, and Z are independently —O, —NH, —S, or —N—(C 1 -C 30 )-alkyl; R 2 is ═O, —OH, —SO 2 , —SO, or —SOCH 3 ; R 3 on ring A is —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, —(C 3 -C 20 )-heteroaryl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —(C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl-(C 1 -C 12 )-alkyl, —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen; and R 3 on ring C is hydrogen, —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen, with the proviso that: (i) when R 1 is unsubstituted pyridine or N-substituted pyridine by —(C 1 )-alkyl, X, Y, Z are —NH, R 2 is ═O, A is quinoline or pyridine, B is phenyl or pyridine, C is phenyl, R 3 on ring C is hydrogen, then R 3 on ring A is not —COO—(C 1 )-alky, not —CO—(C 1 )-alkyl, not —N—[(C 1 )-alkyl] 2 , not —COOH, not —CN, and not —F; (ii) when the compound has the structure of Formula III, R 1 is unsubstituted pyridine, N-substituted pyridine by —(C 1 -C 3 )-alkyl, or pyrimidine substituted by —(C 1 )-alkyl and —NH 2 , X, Y, Z are —NH, R 2 is ═O, then R 4 is not halogen, not —(C 1 )-alkyl, not —O—(C 1 )-alkyl, not —NH 2 , and not —N—[(C 1 )-alkyl] 2 (iii) when R 1 is unsubstituted pyridine, unsubstituted quinoline, quinoline substituted by —NH 2 , —NO 2 , or —N—[(C 1 )-alkyl] 2 , or pyrimidine substituted by —(C 1 )-alkyl and —NH 2 , X, Y, Z are —NH, R 2 is ═O, A is pyridine, naphthalene, or pyrimidine, B is phenyl, C is phenyl, R 3 on ring C is hydrogen, then R 3 on ring A is not —(C 1 -C 2 )-alkyl and not —NH 2 ; (iv) when R 1 is acridine, X, Y, Z are —NH, R 2 is ═O, A is pyridine or pyrimidine substituted by —(C 1 )-alkyl and —NH 2 , B is phenyl, C is phenyl, R 3 on ring C is hydrogen, then R 3 on ring A is not —(C 1 )-alkyl; and (v) when A is pyridine or quinazoline, B is phenyl, C is phenyl, X is —O, Z is —O or —NH, Y is —NH, R 2 is ═O, R 3 on ring A is pyrimidine, phenyl, or —CONH—(C 1 )-alkyl, R 3 on ring C is halogen or —(C 1 )-alkyl, then R 1 is not —(C 1 )-alkyl, not —(C 2 -C 3 )-alkyl substituted by —N—[(C 1 )-alkyl] 2 or —(C 4 )-heterocycloalkyl.
  2. 2 . The compound according to claim 1 , wherein ring B is a six-membered aryl.
  3. 3 . The compound according to claim 2 , wherein ring B is phenyl.
  4. 4 . The compound according to claim 1 , wherein ring B is an N-containing heteroaryl mono- or bicyclic ring system containing one or more N atoms.
  5. 5 . The compound according to claim 4 , wherein ring B is pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, quinazoline, isoquinoline, naphthyridine, indole, isoindole, cinnoline, phthalazine, quinoxaline, pteridine, purine, or benzimidazole.
  6. 6 . The compound according to claim 1 , wherein ring B is an aryl bicyclic ring system.
  7. 7 . The compound according to claim 6 , wherein ring B is naphthalene.
  8. 8 . The compound according to claim 1 , wherein ring A is pyridine.
  9. 9 . The compound according to claim 1 , wherein ring A is quinoline.
  10. 10 . The compound according to claim 1 , wherein R 3 on ring A is-CN, —N—[(C 1 -C 12 )-alkyl] 2 , or —(C 3 -C 12 )-heterocycloalkyl.
  11. 11 . The compound according to claim 1 , wherein R 3 on ring C is hydrogen, —(C 1 -C 30 )-alkyl, or halogen.
  12. 12 . The compound according to claim 1 , wherein R 1 is phenyl, pyridine, pyrimidine, pyridazine, —(C 3 -C 12 )-cycloalkyl, or —(C 3 -C 12 )-heterocycloalkyl, optionally substituted by one or more —(C 1 -C 12 )-alkyl, —NH 2 , —CN, halogen, —(C 3 -C 20 )-cycloalkyl, or —(C 3 -C 20 )-heteroaryl.
  13. 13 . The compound according to claim 1 , wherein X, Y, and Z are independently —O, —NH—, or —N—(C 1 -C 30 )-alkyl.
  14. 14 . A pharmaceutical composition comprising a compound according to Formula I, or an enantiomer, or a pharmaceutically acceptable salt thereof; and an excipient, or a pharmaceutically acceptable enantiomer, or salt thereof, wherein: rings A and C are independently phenyl, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, quinazoline, isoquinoline, naphthalene, naphthyridine, indole, isoindole, cinnoline, phthalazine, quinoxaline, pteridine, purine, or benzimidazole; ring B is six-membered aryl, N-containing heteroaryl mono- or bicyclic ring system containing one or more N atoms, or aryl bicyclic ring system; R 1 is selected from the group consisting of-(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, or —(C 3 -C 20 )-heteroaryl groups optionally substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen; X, Y, and Z are independently —O, —NH, —S, or —N—(C 1 -C 30 )-alkyl; R 2 is ═O, —OH, —SO 2 , —SO, or —SOCH 3 ; R 3 on ring A is —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, —(C 3 -C 20 )-heteroaryl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —(C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl-(C 1 -C 12 )-alkyl, —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen; and R 3 on ring C is hydrogen, —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen, wherein the compound, or the enantiomer, polymorph, or pharmaceutically acceptable salt thereof, is in an amount effective to increase a suppressive immune response in a subject in need thereof when administered to the subject.
  15. 15 . A method of increasing an immune suppressive response in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 14 .
  16. 16 . The method of claim 15 , wherein the subject has an inflammatory disorder or disease, an autoimmune disorder or disease, chronic infection, transplant rejection, or graft-versus-host disease.
  17. 17 . The method of claim 16 , wherein the inflammatory disorder or disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, anklosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopeni purpura (ATP), Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn's disease, Dego's disease, dermatomyositis, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Grave's disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Iga nephropathy, insulin dependent diabetes (Type I), juvenile arthritis, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, obesity, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis.
  18. 18 . The method of claim 16 , wherein the autoimmune disorder or disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia areata, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenia purpura (ATP), Crohn's disease multiple sclerosis, and myasthenia gravis.
  19. 19 . The method of claim 15 , wherein the immune suppressive response 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).
  20. 20 . The method of claim 19 , wherein the immune suppressive function of nTreg is the secretion of one or more anti-inflammatory cytokines.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 16/645,293 filed Mar. 6, 2020, which is a National Phase application under 35 U.S.C. § 371 of PCT/US2018/049715, filed Sep. 6, 2018, which claims benefit of and priority to U.S. Provisional Application Nos. 62/555,141 filed on Sep. 7, 2017, 62/657,345 filed on Apr. 13, 2018, and 62/659,870 filed on Apr. 19, 2018, which are incorporated by reference in their entirety. REFERENCE TO SEQUENCE LISTING The Sequence Listing XML submitted as a file named “AURI_2017_030_CON_ST26.xml,” created on Mar. 11, 2024, and having a size of 6,331 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.834(c)(1). FIELD OF THE INVENTION The invention is generally directed to compositions and methods for selective activation of Akt3 activity, and methods of use thereof for modulating regulator T cells. BACKGROUND OF THE INVENTION Regulatory T cells (Tregs) are a subset of CD4+ T cells that suppress immune responses and are essential mediators of self-tolerance and immune homeostasis (Sakaguchi, et al., Cell, 133, 775-787 (2008)). Depletion or inactivation of Tregs results in the development of severe autoimmunity (Sakaguchi, et al., J. Immunol., 155, 1151-1164 (1995)), and their accumulation inhibits anti-tumor immunity (Dannull, et al., The Journal of clinical investigation, 115, 3623-3633 (2005)). Tregs are characterized by Foxp3 expression, a transcription factor belonging to the Forkhead Box family of transcription factors. The Foxp3 is a master regulator of Tregs, as it is necessary for their development and function (Hori, Science, 299, 1057-1061 (2003); Fontenot, et al., Nat Immunol., 4(4):330-6 (2003). Epub 2003 Mar. 3; Khattri, et al., Nat Immunol., 4(4):337-42 (2003). Epub 2003 Mar. 3)). There are two major types of Tregs: thymus-derived Tregs (or natural Tregs (nTregs)) that constitute 5-10% of the total peripheral CD4+ T cells, and peripheral TGFβ-induced Tregs (iTregs). Both types are shown to have immunosuppressive properties mediated via several processes that involve immunosuppressive soluble factors or cell contact (Bluestone, et al., Nat Rev Immunol, 3, 253-257 (2003); Glisic, et al., Cell and Tissue Research, 339, 585-595 (2010); Hori, Science, 299, 1057-1061 (2003); Sakaguchi, Cell, 101, 455-458 (2000); Sakagushi, et al., Curr. Top Microbiol. Immunol., 305, 51-66 (2006); Sakagushi, et al., Immunol., Rev., 212, 8-27 (2006); (Schmidt, et al., Front Immunol., 3:51 (2012)). However, the molecular mechanisms by which nTreg and iTreg develop and then exhibit non-redundant roles to suppress the immunity are not fully understood (Dipica, et al., Immunity, 35(1):109-122 (2011)). PI3K-Akt signaling affects many processes and is central to many signaling pathways. Akt phosphorylation and kinase activity are induced by PI3K activation, which is, in turn, induced by several growth factor receptors, TCR, CD28, and IL-2R, among many others (Parry, et al., Trends in Immunology, 28, 161-168 (2007)). In mammals, there are three Akt isoforms, namely Akt1, Akt2, and Akt3, encoded by three independent genes. In vitro, these isoforms appear to have redundant functions, as different extracellular inputs can induce similar Akt signaling patterns (Franke, Science 1, pe29-(2008)). However, isoform-specific knockouts show unique features and their involvement in diseases and physiological conditions is different (Boland, et al., American Journal of Human Genetics, 81, 292-303 (2007); DeBosch, et al., J. Biol. Chem, 281, 32841-32851 (2006); Emamian, et al., Nat Genet, 36, 131-137 (2004); Garofalo, et al., The Journal of clinical investigation, 112, 197-208 (2003); George, et al., Science, 304, 1325-1328 (2004); Nakatani, et al., The Journal of Biological Chemistry, 274, 21528-21532 (1999); Tschopp, et al., Development (Cambridge, England), 132, 2943-2954 (2005); Yang, et al., J. Biol. Chem., 278, 32124-32131 (2003)). Studies have shown that Akt1 and Akt2 can negatively regulate the transcriptional signature of Treg, thereby selectively affecting Treg lineage differentiation (Sauer, et al., Proceedings of the National Academy of Sciences, 105, 7797-7802 (2008a)). Additionally, although it was shown that inhibition of Akt1 and Akt2 isoforms increase Foxp3 expression in TGFβ induced iTregs (Sauer, et al., Proc. Natl. Acad. Sci. USA, 105, 7797-7802 (2008b)), the mechanism remained unclear. Another finding shows that deletion of Akt2 resulted in defective iTh17 cell differentiation but preserved nTh17 cell development (Kim, et al., Nat Immunol., 14(6):611-8 (2013) Epub 2013 May 5). Further, Akt3 is also expressed in immune cells and the spinal cord of Akt3 knockout mice have decreased numbers of Foxp3+ regulatory T cells compared with wild type mice (Tsiperson, et al., J Immunol., 190(4):1528-39 (2013) Epub 2013 Jan. 18)). Thus, although some studies have examined the relevance of Akt isoform expression on T cell biology (Carso