WO2018232238A1 - Agent thérapeutique contre la sclérose tubéreuse de bourneville (stb) - Google Patents

Agent thérapeutique contre la sclérose tubéreuse de bourneville (stb) Download PDF

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WO2018232238A1
WO2018232238A1 PCT/US2018/037753 US2018037753W WO2018232238A1 WO 2018232238 A1 WO2018232238 A1 WO 2018232238A1 US 2018037753 W US2018037753 W US 2018037753W WO 2018232238 A1 WO2018232238 A1 WO 2018232238A1
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set forth
subject
apx2009
apx2014
apx3330
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Mark R. Kelley
Melissa L. FISHEL
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Indiana University Research And Technology Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone

Definitions

  • the present disclosure relates generally to compounds, and methods and uses of compounds and pharmaceutical compositions thereof, for preventing the progression and/or onset of tuberous sclerosis complex (TSC) and its various disease traits. More particularly, it has been found that APE1 inhibitors, e.g., APX3330 and APX2009, can be used as useful therapeutic agent(s) for TSC disease.
  • APE1 inhibitors e.g., APX3330 and APX2009
  • Tuberous sclerosis complex is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs.
  • TSC Tuberous sclerosis complex
  • the incidence and severity of the various aspects of TSC can vary widely between individuals— even between identical twins.
  • the aspects of TSC that most strongly impact quality of life are generally associated with the brain: seizures, developmental delay, intellectual disability and autism.
  • This disorder affects as many as 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders.
  • TSC can manifest in so many different ways, diagnosis is generally made when physicians identify any two major features of TSC in one individual.
  • One major feature is cardiac rhabdomyoma, an abnormal growth in the heart muscle generally found in young children and sometimes found by ultrasound examination during pregnancy.
  • Other major features include: specific abnormal skin growths or skin pigmentation, specific non-malignant tumors or growths such as subependymal nodules or subependymal giant cell astrocytomas (SEGAs) in the brain, lymphangioleiomyomatosis (LAM) in the lungs, angiomyolipomas in the kidney(s), and tubers in the brain or hamartomas in the eye.
  • SEGAs subependymal nodules or subependymal giant cell astrocytomas
  • LAM lymphangioleiomyomatosis
  • angiomyolipomas in the kidney(s)
  • tubers in the brain or hamartomas in the eye.
  • TSC can also be diagnosed by genetic testing.
  • the growth of tumors resulting from TSC is not as severely unregulated as in cancer, but these tumors may still cause serious problems. Tumors that grow in the brain can block the flow of cerebral spinal fluid in the spaces (ventricles) in the brain. This can lead to behavioral changes, nausea, headaches or a number of other symptoms.
  • the tumors are usually at their largest at birth and then decrease in size as the individual gets older. These heart tumors, called cardiac rhabdomyomas, can cause problems at birth if they are blocking the flow of blood or causing severe arrhythmia.
  • the tumors in the eyes are not as common, but can present problems if they grow and block too much of the retina.
  • the tumors in the kidney renal angiomyolipomas
  • the tumors in the kidney can become so large they eventually disrupt normal kidney function or begin to bleed internally.
  • TSC is caused by mutations in either of two genes, TSC1 or TSC2.
  • the proteins encoded by TSC1 and TSC2 form a complex that inhibits mTOR complex 1 (mTORCl), which in turn promotes cell growth.
  • mTORCl mTOR complex 1
  • Loss of function of TSC1/TSC2 leads to hyperactivation of mTORCl, a major cause of TSC pathology.
  • Normalization of mTORCl signaling using mTOR inhibitors is observed to ameliorate some of the manifestations of TSC in the clinic, including tumor formation and epilepsy.
  • mTOR inhibitors have been conventionally used as the first- line therapy to treat TSC and are effective at shrinking tumours and delaying disease progression.
  • mTOR inhibitors are cytostatic in drug activity, meaning that TS-tumor cells regrow once the treatment regime has ended.
  • APE1 inhibition leads to a reduction in angiogenic drive, tumor formation, proliferation and cell survival in tuberous sclerosis complex (TSC) cell line models.
  • TSC tuberous sclerosis complex
  • the present disclosure further identified the mTOR pathway as a potential target of APEl redox regulation, such that blocking with the APEl inhibitors of the present disclosure, alone or potentially in combination with a mTOR inhibitor, would be a strong combination therapy for treating TSC.
  • the present disclosure is directed to a method of reducing angiogenic drive in a subject having or suspected of having tuberous sclerosis complex (TSC), the method comprising administering to the subject at least one of 3-[(5-(2,3-dimethoxy- 6-methyl l,4-benzoquinoyl)]-2-nonyl-2-proprionic acid, (APX3330), methoxy-l,4-dioxo-l,4- dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3- methoxy-l,4-dioxo-l,4-dihydronapthalen -2-yl)methylidene]-N,N-dimethylpentanamide] (APX2007), (2E)-2-[(3-methoxy- 1 ,4-dioxo-l ,4-dihydr
  • the present disclosure is further directed to a method of reducing tumor formation in a subject having or suspected of having tuberous sclerosis complex (TSC), the method comprising administering to the subject at least one of 3-[(5-(2,3-dimethoxy-6- methyl l,4-benzoquinoyl)]-2-nonyl-2-proprionic acid, (APX3330), methoxy-l,4-dioxo-l,4- dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3- methoxy-l,4-dioxo-l,4-dihydronapthalen -2-yl)methylidene]-N,N-dimethylpentanamide] (APX2007), (2E)-2-[(3-methoxy- 1 ,4-dioxo-l ,4-dihydronapthalen -2-y
  • the present disclosure is further directed to a method of reducing tumor proliferation in a subject having or suspected of having tuberous sclerosis complex (TSC), the method comprising administering to the subject at least one of 3-[(5-(2,3-dimethoxy-6- methyl l,4-benzoquinoyl)]-2-nonyl-2-proprionic acid, (APX3330), methoxy-l,4-dioxo-l,4- dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3- methoxy-l,4-dioxo-l,4-dihydronapthalen -2-yl)methylidene]-N,N-dimethylpentanamide] (APX2007), (2E)-2-[(3-methoxy- 1 ,4-dioxo-l ,4-dihydronapthalen -2-y
  • the present disclosure is further directed to a method of treating tuberous sclerosis complex (TSC) in a subject, the method comprising administering to the subject at least one of 3-[(5-(2,3-dimethoxy-6-methyl l,4-benzoquinoyl)]-2-nonyl-2-proprionic acid, (APX3330), methoxy- 1 ,4-dioxo-l ,4-dihydronaphthalen-2-yl)methylidene]-N,N- diethylpentanamide] (APX2009), (2E)-2-[(3-methoxy-l,4-dioxo-l,4-dihydronapthalen -2- yl)methylidene]-N,N-dimethylpentanamide] (APX2007), (2E)-2-[(3-methoxy-l,4-dioxo-l,4- dihydronapthalen -2-yl)methylidene]
  • FIG. 1 depicts the dual functions of APEl/Ref-1.
  • APEl/Ref-1 is a multifunctional protein involved in redox signaling and DNA repair.
  • the redox signaling function (Ref-1) is responsible for reduction of oxidized cysteine residues in certain transcription factors (TF's), leading to increased transcriptional activity and upregulation of genes involved in cell growth, inflammation, angiogenesis, and other cellular functions.
  • the DNA repair function (APE1) is responsible for the endonuclease activity in base excision repair, cutting the phosphodiester backbone of DNA at abasic sites created by glycosylases. These cuts allow the abasic sites to be replaced with appropriate nucleotide bases, completing the DNA base excision repair process.
  • FIG. 2 A depicts Ref-1 signaling as a node in tumor cells and potential inhibitors in related pathways.
  • Ref-1 redox signaling promotes the transactivation of transcription factors such as STAT3, HIF- ⁇ , and NF- ⁇ .
  • Inhibiting Ref-1 with APX3330 decreases the expression of downstream genes, leading to tumor cell growth arrest and/or death.
  • other methods for inhibiting the signaling pathways affected by Ref-1, as well as the enzymes that are upregulated by these pathways have been shown to enhance the cytotoxic and cytostatic effects of Ref- 1 inhibition.
  • FIG. 2B depicts Ref-1 signaling as a drug target for tuberous sclerosis (TS).
  • FIGS. 3A-3D depict Ref-1 expression and STAT3, HIF- ⁇ , and NF-kB activity being enhanced in Tsc2-/- MEFs.
  • FIG. 3 A Ref-1 mRNA and protein expression was determined in Tsc2 +/+ and _/ ⁇ MEFs.
  • FIG. 3B STAT3,
  • FIG. 3C HIF- ⁇
  • FIG. 3C HIF- ⁇
  • NF-kB luciferase transcription assays were carried out in Tsc2-/- MEFs subjected over-night to 1 % oxygen (hypoxia) with either wild-type TSC2 re-expressed (“WT TSC2") or after treatment with APX3330 (25, 50, 100 ⁇ ), as indicated.
  • FIGS. 4A-4C depict targeting HIF- ⁇ , STAT3, NF-kB, Ref-1 impairs tumor formation of TS cell line models.
  • Tumor formation assays were carried out in (FIG. 4A) AML cells (621-102) that had HIF- ⁇ or STAT3 shRNA knockdown and (FIG. 4B) Tsc2 _/" MEFs treated with the NF-kB inhibitor, JSH23 (10 ⁇ ).
  • FIG. 4C depicts Tsc2 _/" MEFs treated with APX3330 (25, 50, 100 ⁇ ), as indicated. Representative image of the tumor spheroid is shown.
  • FIGS. 5A-5D depict APX3330 (25, 50, 100 ⁇ ), as indicated, blocking wound closure of TSC2-/- MEFs.
  • FIG. 5A depicts wound closure blocking measured at 18 hours.
  • FIG. 5B depicts wound closure blocking measured at 24 hours.
  • FIG. 5C depicts wound closure blocking measured at and 42 hours.
  • FIGS. 6A & 6B depict APX3330 inhibiting cell migration in TSC 2 _/" MEFs.
  • FIG. 7 depicts that STAT3 inhibition impairs vasculature mimicry in AML cells.
  • FIGS. 8A-8C depicts that APX3330 blocks vasculature mimicry in Tsc2 _/"
  • FIGS. 9A & 9B depict that mTOR inhibition is not sufficient to block HIF-la or STAT3 in TSC2 _/ ⁇ MEFs.
  • FIG. 9A HIF-la luciferase transcription assays were carried out in TSC2 _/" MEFs subjected over-night to 1 % oxygen (hypoxia) with either wild-type TSC2 re- expressed or after treatment with rapamycin (100 nM), APX3330 (25, 50, 100 ⁇ ) or APX2009 (10, 20, 30 ⁇ ), as indicated.
  • FIG. 9B STAT3-P and ribosomal protein S6 (rpS6) phosphorylation was determined from TSC2 _/ ⁇ MEFS that has been treated with the mTOR inhibitor (Ku-0063794) for up to 24 hours.
  • FIGS. 10A & IOC depict efficacy of APX3330 in controlling growth of ELT3 tumor growth in vivo: Bodyweight (FIG. 10A) and Dose (FIG. IOC).
  • FIG. 10B depicts cytotoxicity of APX3330 treatment on cells in culture.
  • FIGS. 10D-10I depict cytotoxicity of APX3330, APX2009 or APX2014 in combination with napabucasin on cells in culture.
  • APEl/Ref-1 Apurinic/Apyrimidinic Endonuclease/reduction-oxidation (Redox) Factor- 1 (APEl/Ref-1) was originally identified as an endonuclease that plays a key role in the Base Excision Repair (BER) pathway's repair of oxidative and alkylating damage. Later, APEl/Ref-1 was recognized as a redox signaling protein that modulates the activity of certain transcription factors. Since then, additional functions of APEl/Ref-1 have been uncovered. APEl/Ref-1 's duality and pivotal positions in repair and redox activities make it a unique target for therapeutic modulation.
  • BER Base Excision Repair
  • APEl/Ref-1 endonuclease activity is vital to the DNA damage response in all cells, making APEl/Ref-1 a crucial factor in cellular function and survival.
  • the repair function has been conserved from E. coli to humans; however, the redox signaling function is observed only in mammals.
  • APEl/Ref-1 redox signaling affects numerous transcription factors including STAT3, fflF-la, NF- ⁇ , AP-1, p53, and a few others.
  • APEl/Ref-1 redox signaling is a highly regulated process that reduces oxidized cysteine residues in specific transcription factors as part of their trans activation (FIG. 1).
  • APEl/Ref-1 expression is increased in many tumor types, and that change is associated with increased growth, migration, and drug resistance in tumor cells as well as decreased patient survival.
  • APEl/Ref-1 is seen as a critical node in tumor signaling (FIG. 2A), and thus, is a prime target for anticancer therapy
  • FIG. 2A tumor signaling
  • teasing apart APEl/Ref-1 's activities to create a specific inhibitor that targets only its endonuclease or redox function is challenging.
  • a number of compounds isolated from natural sources have been proposed as Ref-1 redox signaling inhibitors, but none have been shown to directly or specifically inhibit Ref-1 redox signaling.
  • resveratrol is typical of the other compounds; it's in vivo efficacy is sporadic at best due to widely varying bioavailability and low molecular specificity.
  • Curcumin Another presumed natural Ref-1 redox inhibitor, curcumin, has been established as a promiscuous compound, interacting with a variety of molecules to give false-positive results in numerous biological assays. Thus, these are not specific or viable APEl/Ref-1 redox inhibitors.
  • E3330 3-[(5- (2,3-dimethoxy-6-methyl l ,4-benzoquinoyl)]-2-nonyl-2-proprionic acid, (hereinafter "E3330" or “3330” or “APX3330”), and its analogues, has been identified as a specific APEl/Ref-1 redox inhibitor.
  • APX3330 has been extensively characterized as a direct, highly selective inhibitor of Ref-1 redox activity that does not affect the protein's endonuclease activity. Treatment with APX3330 has been found herein to reduce angiogenic drive, tumor formation, proliferation and cell survival, in TSC cell line models.
  • apurinic endonuclease 1/redox factor-1 orchestrates a transcriptional program that is constitutively switched on by reactive oxygen species (ROS) in Tuberous Sclerosis Complex (TSC)-tumour cells.
  • ROS reactive oxygen species
  • TSC Tuberous Sclerosis Complex
  • This transcriptional program drives angiogenesis, metabolic transformation, cell survival, and cell migration/invasion.
  • these activities are not completely restored to normal with conventionally-used mTOR inhibitors, which means an alternative therapeutic strategy to inhibit inflammatory signaling through STAT3/HIF-la/NF-KB is needed.
  • the methods of the present disclosure are directed to administration of an effective amount of 5-(2,3-dimethoxy-6-methyl 1 ,4- benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330)), or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof. More particularly, it is shown herein that APX3330 effectively lead to a reduction in angiogenic drive, tumor formation, proliferation and cell survival in tuberous sclerosis complex (TSC) cell line models.
  • TSC tuberous sclerosis complex
  • mTOR pathway is a potential target of APEl redox regulation, such that blocking either with APX3330 of the present disclosure, alone or potentially in combo with a mTOR inhibitor, would be a strong combination therapy for treating TSC.
  • the APEl inhibitor is [(2E)-2-[(3-methoxy-l,4-dioxo- 1,4-dihydronapthalen -2-yl)methylidene]-N,N-diethylpentanamide] (hereinafter "APX2009”) for use as an alternate APEl inhibitor to APX3330 or for use in combination with APX3330.
  • APX2009 [(2E)-2-[(3-methoxy-l,4-dioxo- 1,4-dihydronapthalen -2-yl)methylidene]-N,N-diethylpentanamide]
  • the APEl inhibitor is (2E)-2-[(3-methoxy-l,4-dioxo- 1,4-dihydronapthalen -2-yl)methylidene]-N-methoxypentanamide] (hereinafter "APX2014”) for use as an alternate APEl inhibitor to APX3330 and/or APX2009 or for use in combination with APX3330 and/or APX2009.
  • APX2014 (2E)-2-[(3-methoxy-l,4-dioxo- 1,4-dihydronapthalen -2-yl)methylidene]-N-methoxypentanamide]
  • analogues include, for example, (2E)-2-[(3-methoxy-l,4-dioxo-l,4- dihydronapthalen -2-yl)methylidene]-N,N-dimethylpentanamide] (APX2007) and (2E)-2-(3- methoxy ,4-dioxo ,4-dmydronaphthalen-2-yl)-N,N,2-trimethylprop-2-enamide (APX2032).
  • compositions including APX3330, APX2009, APX2007, APX2014 and/or APX2032 in a form appropriate for the intended application. Generally, this will entail preparing compositions that are essentially free of impurities that could be harmful to a subject.
  • the compound i.e., APX3330, APX2009, APX2007, APX2014 and/or APX2032
  • compositions can be administered orally, intravenously, intramuscularly, intrapleurally or intraperitoneally at doses based on the body weight and degree of disease progression of the subject, and may be given in one, two or even four daily administrations.
  • APX3330, APX2009, APX2007, APX2014 and/or APX2032 is administered in concentrations ranging from about 1 ⁇ to about 100 ⁇ , including from about 5 ⁇ to about 50 ⁇ , and including about 25 ⁇ .
  • APX2009 and/or APX2014 is administered, it can be administered in concentrations ranging from about 3 ⁇ to about 10 ⁇ .
  • compositions of the present disclosure comprise an effective amount of the compound, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Such compositions also are referred to as innocuous.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients also can be incorporated into the compositions.
  • compositions for use in the present disclosure may include classic pharmaceutical preparations. Administration of these compositions according to the present disclosure will be via any common route so long as the target tissue is available via that route. This includes oral, nasal, buccal, rectal, vaginal or topical. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions, as described herein.
  • the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols.
  • APX3330, APX2009, APX2007, APX2014 and/or APX2032 may also be administered parenterally or intraperitoneally.
  • Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form is sterile and is fluid to the extent that easy syringability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • compounds of the present disclosure may be incorporated with excipients and used in the form of non-ingestible mouthwashes and dentifrices.
  • a mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution).
  • the active ingredient may be incorporated into an antiseptic wash containing sodium borate, glycerin and potassium bicarbonate.
  • the active ingredient may also be dispersed in dentifrices, including gels, pastes, powders and slurries.
  • the active ingredient may be added in a therapeutically effective amount to a paste dentifrice that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
  • a paste dentifrice may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
  • the compositions for use in the present disclosure may be formulated in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like.
  • the solution For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences” 15th Edition, pages 1035- 1038 and 1570-1580).
  • Some variation in dosage will necessarily occur depending on the condition of the subject being treated.
  • the person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • preparations should meet sterility, general safety and purity standards as required by FDA and foreign counterpart agencies.
  • the methods described herein can further include administering one or more mTOR inhibitor with APX3330, APX2009, APX2007, APX2014 and/or APX2032.
  • one or more mTOR inhibitor selected from the group consisting of dactolisib, rapamycin, everolimus, AZD8055, temsirolimus, CZ415, PI-103, KU-0063794, torkinib, tacrolimus, ridaforolimus, INK 128, voxtalisib, torin 1, omipalisib, OSI-027, PF-04691502, apitolisib, GSK1059615, gedatolisib, WYE-354, vistusertib, torin 2, MHY1485 and the like, and combinations thereof can be administered with APX3330, APX2009, APX2007, APX2014 and/or APX2032.
  • the methods can further include administering an anti- inflammatory with APX3330, APX2009, APX2007, APX2014 and/or APX2032, for example, anti-inflammatory agents such as anti-IL6 antibodies and/or NFKB inhibitors.
  • the methods can further include administering the APEl/Ref-1 inhibitor in combination with one or more inhibitor(s) of signal transducer and activator of transcription 3 (STAT3) and/or Janus kinase (JAK), which is upstream of STAT3.
  • STAT3 signal transducer and activator of transcription 3
  • JK Janus kinase
  • STAT3 inhibitors include 2-Hydroxy-4-(((4- methylphenyl)sulfonyloxy)acetyl)amino)-benzoic acid/S3I-201, 6-Nitrobenzo[b]thiophene-l,l- dioxide/stattic, OCHROMYCINONE, 4-[[(4-cyclohexylphenyl)methyl][2-[methyl[(2,3,4,5,6- pentafluorophenyl)sulfonyl]amino]acetyl]amino]-benzoic acid (SH-4-54), napabucasin (BBI- 608) and analogues thereof, 4-(N-(4-Cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N- methylphenylsulfonamido)acetamido)-2-hydroxybenzoic acid (BP-1-102), as well as other inhibitors based on the BP
  • JAK inhibitors include Ruxolitinib ("RUX"), Erlotinib, LY3009104, Tofacitibnib, Baricitinib, CYT387, Filgotinib, Lestaurtinib, Pacritinib, and combinations thereof.
  • APX3330 as well as its 2nd generation drugs, APX2009 and APX2014, are used to characterize the oxidative stress and inflammatory response in cells with and without TSC2 expression, to determine whether targeting redox signalling via Ref-1 could be exploited for therapy in TSC.
  • APX3330 as well as its 2nd generation drugs, APX2009 and APX2014, are used to characterize the oxidative stress and inflammatory response in cells with and without TSC2 expression, to determine whether targeting redox signalling via Ref-1 could be exploited for therapy in TSC.
  • FIG. 3 A preliminary data showing that Ref-1 expression was enhanced in TSC2-deficient cells
  • FIGS. 3B-3D data is shown where the Ref-1 inhibitor (APX3330) was effective at blocking HIF- ⁇ , STAT3 and NF-kB activity in Tsc2-/- MEFs and restoring their activity to a level that was comparable to the rescue cell line with TSC2 re-expressed is provided in FIGS. 3B-3D.
  • HIF- ⁇ FIG. 3B
  • STAT3 FIG. 3C
  • NF-kB FIGS. 3B-3D
  • luciferase transcription assays were carried out in Tsc2 _/" mouse embryonic fibroblasts (MEFs) subjected overnight to 1% oxygen (hypoxia) with either wild-type TSC2 re-expressed (“WT TSC2”) or after treatment with APX3330 (25, 50, 100 ⁇ ), as indicated.
  • TSC2 _/" and TSC2 +/+ MEFs were determined using a CyQuant assay (Life Technologies).
  • the ability of TSC2 _/" MEFs to form spheroids in soft agar was determined using tumor formation assays. Tumor formation assays were carried out in AML cells (621-102) that had HIF- ⁇ or STAT3 shRNA knockdown (FIG. 4A) and TSC2 _/" MEFs treated with the NF-kB inhibitor, JSH23 (10 ⁇ ) (FIG. 4B).
  • Metabolic reprogramming was further analyzed through changes in gene- expression of selected HIF- ⁇ targets in both cell line models under hypoxia (1% oxygen) and normoxia (21% oxygen) conditions.
  • AML cells (621-102) in MATRIGEL were subjected to 1% O2 for 18 hours in the presence or absence of either the mTOR inhibitor (Ku- 0063794) or STAT3 inhibitor (FLLL31) (DMSO used as a no-drug control) (FIG. 7).
  • Average vessel length measured using Angiotool software, as well as number of branch points and junctions, was dramatically impaired with FLLL31, but not with Ku-0063794 (results not shown).
  • APX3330 blocks vasculature mimicry in TSC2 _/ ⁇ MEFs.
  • HIF- ⁇ luciferase transcription assays were then carried out in Tsc2-/- MEFs subjected overnight to 1% oxygen (hypoxia) with either wild-type TSC2 re-expressed or after treatment with rapamycin (100 nM), APX3330 (25, 50, 100 ⁇ ) or APX2009 (10, 20, 30 ⁇ ), as indicated in FIG. 9A.
  • the 2nd generation inhibitor APX2009 was more potent at blocking HIF- ⁇ activity at much lower concentrations (FIG. 9A).
  • mTOR inhibition with rapamycin was not sufficient to restore HIF- ⁇ activity to a level that was equivalent to when wild-type TSC2 was re-expressed.
  • mTOR inhibition (with Ku- 0063794) was ineffective at blocking STAT3 Tyr705 phosphorylation, a phosphorylation event that correlates with STAT3 activity (FIG. 9B).
  • STAT3-P and ribosomal protein S6 (rpS6) phosphorylation was determined from TSC2 _/ ⁇ MEFs that has been treated with the mTOR inhibitor (Ku-0063794) for up to 24 hours.
  • ELT3 -xenograft mice were treated with vehicle, 25 mg/kg BID and 50 mg/kg BID APX3330, and 25 mg/kg BID APX2009.
  • FIG. 10A animals steadily increased bodyweight in all treatment conditions for the duration of the study.
  • FIG. 10B all treatments were well tolerated for the duration of the study as no cytotoxic effect on cells in culture was observed.
  • FIG. IOC 50 mg/kg APX3330 and 25 mg/kg APX2009 inhibited tumor growth.

Abstract

L'invention concerne des méthodes et des utilisations d'inhibiteurs d'APE1 et de compositions pharmaceutiques associées pour prévenir l'apparition et/ou l'évolution d'une sclérose tubéreuse de Bourneville (STB) et de ses diverses caractéristiques pathologiques.
PCT/US2018/037753 2017-06-16 2018-06-15 Agent thérapeutique contre la sclérose tubéreuse de bourneville (stb) WO2018232238A1 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
US20100285008A1 (en) * 2007-09-26 2010-11-11 Indiana University Research And Technologhy Corporation Benzoquinone derivative e3330 in combination with chemotherapeutic agents for the treatment of cancer and angiogenesis

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US20100285008A1 (en) * 2007-09-26 2010-11-11 Indiana University Research And Technologhy Corporation Benzoquinone derivative e3330 in combination with chemotherapeutic agents for the treatment of cancer and angiogenesis

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