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WO2008012031A2 - Bloqueurs de gsk3 de prévention et de traitement de pemphigus vulgaire - Google Patents

Bloqueurs de gsk3 de prévention et de traitement de pemphigus vulgaire Download PDF

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Publication number
WO2008012031A2
WO2008012031A2 PCT/EP2007/006464 EP2007006464W WO2008012031A2 WO 2008012031 A2 WO2008012031 A2 WO 2008012031A2 EP 2007006464 W EP2007006464 W EP 2007006464W WO 2008012031 A2 WO2008012031 A2 WO 2008012031A2
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WIPO (PCT)
Prior art keywords
gsk3
gsk3β
blocker
pemphigus vulgaris
compound
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Ceased
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PCT/EP2007/006464
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WO2008012031A3 (fr
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Eliane Mueller
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Universitaet Bern
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Universitaet Bern
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Publication of WO2008012031A3 publication Critical patent/WO2008012031A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to the prevention and treatment of pemphigus vulgaris using blockers of glycogen synthase kinase 3 (GSK3).
  • GSK3 glycogen synthase kinase 3
  • Pemphigus vulgaris is an autoimmune blistering disease that affects skin and mucous membranes in man and domestic animals. It is characterized by auto-antibody binding to the desmosomal cadherin desmoglein (Dsg) 3 that results in suprabasal loss of intercellular adhesion in skin and mucous membranes (Amagai et al., Cell, 67, 869-877, 1991). Most PV patient's antibodies target the adhesive interface between juxtaposed Dsg3 molecules of adjacent cells, and are thought to disrupt their trans-adhesion by steric hindrance (Tsunoda et al., J Immunol, 170, 2170-2178, 2003).
  • Glycogen synthase kinase 3 (GSK3)
  • GSK3 is a multifunctional serine/threonine kinase. It exists in two isoforms, GSK3 ⁇ and GSK3 ⁇ that are encoded by different genes. GSK3 is relatively unique among kinases because it is generally constitutively active in cells, and deactivation is responsible for propagation of intracellular signals. The two isoforms share high homology in their catalytic domain, and similar but not absolutely identical biological functions.
  • both GSK3 ⁇ and GSK3 ⁇ are inhibited by protein kinase B ( Toker and Yoeli-Lerner, Cancer Res, 66, 3963-3966, 2006) resulting in activation of proteins regulating cell cycle and apoptosis, while only GSK3 ⁇ is inhibited by the canonical Wnt signaling pathway (Willert and Jones, Genes Dev, 20, 1394-1404, 2006) that promotes nuclear translocation of ⁇ -catenin and plakoglobin. Importantly, it was never shown before that this pathway is affected by PV antibodies.
  • the present invention relates to a method of preventing and treating pemphigus vulgaris comprising administering a GSK3 blocker, and the use of such blockers in said prevention and treatment and in the manufacture of medicaments for preventing and treating pemphigus vulgaris.
  • a GSK3 blocker is a GSK3 ⁇ blocker, in particular a blocker which is selective for GSK3 ⁇ , i.e. which selectively reduces enzyme activity of GSK3 ⁇ but not to a reasonable extent of GSK3 ⁇ .
  • the invention further relates to a method of screening for a compound effective in the prevention and treatment of pemphigus vulgaris comprising contacting a candidate compound with a GSK3, and choosing candidate compounds which selectively reduce activity of GSK3, preferably of GSK3 ⁇ .
  • the invention further relates to compounds selected by these methods of screening.
  • Fig. 1 Nuclear PG is reduced in PV antibody (PVIgG)-treated mouse kerati oocytes.
  • Fig. 2 PVIgG upregulate c-Myc in keratinocyte cultures and in PV patients.
  • C Consecutive sections of paraffin embedded biopsies from six PV patients (PV-1 to PV-6) and healthy donors (C and C-om (oral mucosa)) were stained for c-Myc, counterstained with Hoechst.
  • biopsies from healthy donors, patients with other autoimmune bullous diseases such as pemphigus foliaceous (PF) and bullous pemphigoid (BP) as well as chronic eczematous dermatitis were also investigated.
  • C-Myc positive cells in the dermis likely are leukocytes as judged from H&E stains (data not shown) which is consistent with their absence from non-lesional skin (PV-6). Arrows point to faint c-Myc staining in control skin. Scale bars, 200mm.
  • PG is a suppressor of c-Myc.
  • FIG. 1 Graphs show reporter gene assays using the human c-Myc promoter transfected into mouse keratinocytes with indicated plasmids. The ratio of firefly over renilla luciferase activity (F/R) is indicated. One representative experiment of at least four independent experiments done in single measures per cell type is shown. PG ⁇ C, ⁇ N and ARM lack the C-terminal, N-terminal domain or both, respectively.
  • FIG. 1 Top panel: scheme of the mouse c-Myc promoter and TCF/LEF binding site. Gray bars indicate positions of primer sets relative to the transcription initiation site used to amplify precipitated DNA by Q-PCR.
  • Chromatin immunoprecipitation using indicated antibodies for immunoprecipitation.
  • Graphs depict relative amounts of amplification products (y axis: relative DNA amount) obtained by Q-PCR compared to control IgG with indicated primer sets. One of three independent experiments measured in duplicates is shown. Error bars indicate the range.
  • Fig. 4 Blister formation in neonatal mice is prevented by c-Myc inhibitors as demonstrated by a passive transfer study
  • Fig. 5 Blister formation in neonatal mice is prevented by GSK3 inhibitors as demonstrated by a passive transfer study showing that activated GSK3 accounts for loss of intercellular adhesion.
  • the present invention relates to a method of preventing and treating pemphigus vulgaris comprising administering a GSK3 blocker, and the use of such blockers in said prevention and treatment and in the manufacture of medicaments for preventing and treating pemphigus vulgaris.
  • the invention relates to a method of preventing and treating pemphigus vulgaris comprising administering a GSK3 ⁇ blocker, and the use of such blockers in said prevention and treatment and in the manufacture of medicaments for preventing and treating pemphigus vulgaris.
  • GSK3 ⁇ blockers which are selective for GSK3 ⁇ , i.e. which selectively reduce enzyme activity of GSK3 ⁇ but not to a reasonable extent of GSK3 ⁇ .
  • GSK3 blockers are compounds which reduce the enzyme activity of a GSK3, or inhibit the production of GSK3 or the activation of GSK3 from its latent form, or inhibit the interaction between GSK3 and its activator axin (Willert and Jones, Genes Dev, 20, 1394-1404, 2006).
  • Preferred GSK3 blockers are compounds which reduce the enzyme activity of
  • GSK3 ⁇ or inhibit the production of GSK3 ⁇ or the activation of GSK3 ⁇ from its latent form, or inhibit the interaction between GSK3 ⁇ and axin.
  • GSK3 production can be inhibited by anti-sense oligodeoxynucleotides or siRNAs to the GSK3 isoforms, particularly to GSK3 ⁇ .
  • GSK3 blockers of the invention may belong to the class of inorganic compounds, e.g. lithium salts, or organic compounds, e.g.
  • polypeptides or small organic compounds preferably thiadiazolidinones, inositol-phosphate phosphatases, paullones (lndolo[3,2- d][1]benzazepines), 6-bromo-substituted indirubins (indigo isomer) or also maleimides.
  • GSK3 blockers are widely known. GSK3 blockers are, for example, disclosed in Meijer L. et al., Trends in Pharmacological Sciences, Vol. 25 No. 9, September 2004 and in Patent Applications WO06000589, WO04098607, WO03106455, WO05026155, WO05026159, WO02066480, WO03053444, WO04055009, WO05027823, WO06001754,
  • WO05083105 WO0144206, WO0144246, WO0210357, WO0220495, WO0224893, WO03068932, WO03074072, WO04018455, WO04037791 , WO05039485, WO9965897, WO05021025, WO04016612, WO04016613, WO04043953, WO04056368, WO05005438, WO05012262, WO05012298, WO05042525, WO05075468, WO05116025, WO04074428, WO04018473, WO06024858, WO0152862, WO0152865, WO03037869, WO03037877, WO03037891 , WO05012304, WO05012307, WO05041959, WO06031969, WO06032023, WO04037777, WO
  • Preferred GSK3 blockers according to the invention are:
  • lithium salts such as LiCI
  • lithium mimetics such as mangan salts
  • antibodies and antibody fragments to GSK3 such as human or humanized antibodies or single chain antibodies to GSK3
  • GSK3 ⁇ blockers are: - NP031112
  • One aspect of the invention relates to a method of preventing and treating pemphigus vulgaris comprising administering GSK3 blockers as defined hereinbefore in a quantity effective against pemphigus vulgaris to a mammal in need thereof, for example to a human requiring such treatment.
  • the treatment may be for prophylactic or therapeutic purposes.
  • the GSK3 blocker is preferably in the form of a pharmaceutical preparation comprising the GSK3 blocker in chemically pure form and optionally a pharmaceutically acceptable carrier and optionally adjuvants.
  • the GSK3 blocker is used in an amount effective against pemphigus vulgaris.
  • the dosage of the active ingredient depends upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, the mode of administration, and whether the administration is for prophylactic or therapeutic purposes.
  • the daily dose administered is from approximately 1 mg to approximately 500 mg, preferably from approximately 10 mg to approximately 100 mg
  • the daily dose of a GSK3 antibody administered is from approximately 0.1 mg to approximately 50 mg, preferably from approximately 1 mg to approximately 10 mg.
  • compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, for parenteral administration, such as subcutaneous, intravenous, or intramuscular or topical administration are considered.
  • the pharmaceutical compositions comprise from approximately 1 % to approximately 95% active ingredient, preferably from approximately 20% to approximately 90% active ingredient.
  • compositions of the GSK3 blockers may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, viscosity-increasing agents, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, and also binders, such as starches, cellulose derivatives and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, flow conditioners and lubricants, for example stearic acid or salts thereof and/or polyethylene glycol.
  • Tablet cores can be provided with suitable, optionally enteric, coatings. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules may contain the active ingredient in the form of granules, or dissolved or suspended in suitable liquid excipients, such as in oils.
  • Transdermal application is also considered, for example using a transdermal patch, which allows administration over an extended period of time, e.g. from one to twenty days.
  • compositions for topical administration e.g. epicutaneous administration, for which preference is given to the use of solutions of the GSK3 blockers, and also suspensions or dispersions, ointments, creams and the like.
  • a suitable solution is a GSK3 blocker in 25% DMSO and 75% 1 ,2-propanediol.
  • Another aspect of the invention relates to the use of GSK3 blockers as described hereinbefore in the treatment of pemphigus vulgaris and in the manufacture of medicaments for treating these diseases.
  • Such medicaments are manufactured by methods known in the art, especially by conventional mixing, coating, granulating, dissolving or lyophilizing.
  • the GSK3 blocker can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations of a GSK3 blocker and one or more other therapeutic agents known in the treatment of pemphigus vulgaris, the administration being staggered or given independently of one another, or being in the form of a fixed combination.
  • Possible combination partners considered are glucocorticosteroids and/or immunesuppressiva such as Azathioprine and/or Myc inhibitors, such as the Myc inhibitors described by Yin et al., Oncogene, 22, 6151-6159, 2003.
  • the invention further relates to a method of screening for a compound effective in the treatment of pemphigus vulgaris comprising contacting a candidate compound with GSK3 and choosing candidate compounds which selectively reduce the activity of GSK3, preferably the activity of GSK3 ⁇ but not to a reasonable extent GSK3 ⁇ .
  • the invention further relates to compounds selected by these methods of screening.
  • Inhibitors of GSK3 activity are identified by contacting a GSK3 with a candidate compound.
  • a control assay with the corresponding GSK3 — in the absence of the candidate compound - is run in parallel.
  • a decrease in activity in the presence of the candidate compound compared to the level in the absence of the compound indicates that the compound is a GSK3 inhibitor.
  • Kinase activity is measured using methods known in the art. For example recombinant active GSK3 ⁇ or ⁇ are incubated with inhibitors to be tested, and GSK3 activity measured using a peptide-based kinase assay (Cross, D.A. et al., Biochem. J. 303, 21-26, 1999).
  • Preferred candidate compounds cause marked decrease of GSK3 ⁇ enzyme activity while having no or only marginal influence on GSK3 ⁇ enzyme activity.
  • GSK3 ⁇ in turn regulates the nuclear trafficking of PG.
  • GSK3 inhibition prevents blister formation or in other words PV antibody binding to Dsg3 induce blister formation via lack of GSK3 inhibition was provided herein by a passive transfer study (Anhalt et al., N. Engl. J.
  • AK23 is a pathogenic PV antibody which targets the adhesive interface between juxtaposed Dsg3 molecules.
  • the mouse monoclonal antibody NAK3 was used as a negative control (Amagai et al., unpublished).
  • NAK3 also targets Dsg3, is unable to induce blisters on its own, but has weak pathogenic activity in combination with other blister-inducing antibodies.
  • AK23 and NAK3 were subcutaneously injected into the lumbar area of neonatal mice that had been pre-injected at the same site with GSK3 inhibitors or vehicle. After 24 hours blisters were observed in PVIgG/vehicle and AK23/vehicle injected mice but not in their siblings pre-treated with GSK3 inhibitors.
  • GSK3 blockers are effective therapeutic agents for the treatment of pemphigus vulgaris.
  • PV antibodies PV antibodies
  • normal human IgG normal human IgG
  • Normal human IgG nhlgG
  • Cytoplasmic/low-detergent soluble membrane and nuclear extracts were prepared as described for keratinocytes by Corsini et al with some modifications (Corsini et al., J. Invest. Dermatol., 107, 720-725, 1996).
  • cytoplasm/membrane fraction a fraction of cells were lysed with hypotonic lysis buffer containing 0.58% NP-40, scraped and centrifuged. The supernatant (referred to as cytoplasm/membrane fraction) was removed. Pelleted nuclei were resuspended with the aid of a 23 gauge needle and additionally centrifuged through a 0.85 M sucrose cushion for 15 min at 11700g to remove nucleus- associated endoplasmic reticulum and cellular debris.
  • Mouse keratinocytes were cultured as described in above. Human keratinocytes from foreskin were a kind gift form CELLnTEC Advanced Cell Systems AG, Switzerland and were cultivated in CnT-07 (CELLnTEC, Switzerland). For quantitative PCR (Q-PCR) total RNA was extracted and analyzed using TaqManTM quantitative RT-PCR technology and primers designed and validated as previously described (KoIIy et al., J Invest Dermatol, 124, 1014-1025, 2005). All samples were normalized against cyclophilin S1 mRNA and results are reported as n-fold change relative to the sample at calcium switch. Analyses were done in duplicates of at least three independent experiments.
  • Total protein lysates were obtained by scraping keratinocytes into SDS loading buffer and nuclear extracts as described in Fig. 1. Lesional and peri-lesional biopsies of skin, scalp and oral mucosa performed for clinical purposes were used according to the rules of the Medical Faculty. All biopsies were fixed with 4% formaldehyde and paraffin embedded. For immunofluorescence analysis, Biopsies were deparaffinized and antigens retrieved by microwaving three times 5 min at 720 watt in 0.01 M sodium citrate buffer pH 6.0. Sections were stained with c-Myc antibody (Upstate Biotechnology) and nuclei counterstained with Hoechst 33258 (H-1398, Molecular Probes).
  • a reporter gene assay was done using the DualLuciferaseTM Reporter Assay System (Promega, Wallisellen, Switzerland).
  • PEI Polyethylenimine
  • 50 ml medium was mixed with 2 mg of DNA per 15 ml of PEI (1 mg/ml), incubated for eight min, mixed with 450 ml medium/10% FCS and added onto cells in six well plates 24 h post seeding. Two hours later cells were washed with PBS, and incubated with fresh medium for 24 h to 28 h prior to lysis. In each case 1.25 ⁇ g for reporter genes (kind gifts of E.
  • Albino DDY mice where subcutaneously injected in the lumbar area with 6mM c-Myc inhibitors (5521700 (MI-1) or 5404711 (MI-3); Chembridge) or vehicle (DMSO/PBS). Two hours later, 15mg PVIgG or nhlgG, or alternatively 75 ⁇ g mouse monoclonal AK23 (Tsunoda et al., J Immunol, 170, 2170-2178, 2003) or NAK3 antibody (M. Amagai, unpublished) were injected in the same area in combination with half the minimal dose of a human PF serum inducing blister formation (Mahoney et al., J. Clin.
  • Biopsies were taken from lesional areas, fixed in 4% buffered formaldehyde over night at 4 0 C and paraffin embedded. Biopsies were deparaffinized and stained with H&E or processed for direct immunofluorescence as described under immunofluorescence analyses. Four animals per treatment (PVIgG, AK23, NAK3, nhlgG, no treatment) each with vehicle or c-Myc inhibitors were analyzed in two independent experiments which showed consistent results (in total 20 animals). Immunofluorescence analysis were as described above.
  • Albino DDY mice where subcutaneously injected in the lumbar area with chemical GSK3 inhibitors, SB216763 (100 mM; 2 mg/g body weight; Calbiochem) and LiCI (200 mg/g body weight) (Beaulieu et al., Proc Natl Acad Sci U S A, 101 , 5099-5104, 2004) or vehicle (DMSO/PBS).
  • GSK3 inhibitors SB216763 (100 mM; 2 mg/g body weight; Calbiochem) and LiCI (200 mg/g body weight)
  • DMSO/PBS vehicle

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Abstract

La présente concerne un procédé de prévention et de traitement de pemphigus vulgaire comprenant l'administration un bloqueur GSK3, et l'utilisation de tels bloqueurs dans ladite prévention et ledit traitement et dans la fabrication de médicaments pour prévenir et traiter le pemphigus vulgaire. En particulier, l'invention concerne un procédé de prévention et de traitement de pemphigus vulgaire comprenant l'administration d'un bloqueur GSK3β, et l'utilisation de tels bloqueurs dans ladite prévention et ledit traitement et dans la fabrication de médicaments pour prévenir et traiter le pemphigus vulgaire. De préférence, on utilise des bloqueurs de GSK3β qui sont sélectifs pour le GSK3β, c'est à dire qui réduisent de manière sélective l'activité enzymatique de GSK3β mais non à un degré raisonnable celle de GSK3α.
PCT/EP2007/006464 2006-07-25 2007-07-20 Bloqueurs de gsk3 de prévention et de traitement de pemphigus vulgaire Ceased WO2008012031A2 (fr)

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EP06015408.5 2006-07-25

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WO2008012031A3 WO2008012031A3 (fr) 2008-04-17

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005086814A2 (fr) * 2004-03-09 2005-09-22 The Uab Research Foundation Procedes et compositions relatifs a la regulation de la production de cytokine par la glycogene synthase kinase 3 (gsk-3)
EP1586318A1 (fr) * 2004-04-05 2005-10-19 Neuropharma S.A.U. Thiazolidinones comme inhibiteurs de GSK-3
WO2007075911A2 (fr) * 2005-12-22 2007-07-05 Yale University Inhibition de la glycogene synthase kinase et procedes de traitement de maladies immunitaires ou autoimmunitaires inflammatoires

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