WO2018136933A1 - Inhibition de la molécule d'interaction stromale 1 (stim1) en tant que co-traitement pour la polykystose rénale (pkrad) de l'adulte - Google Patents

Inhibition de la molécule d'interaction stromale 1 (stim1) en tant que co-traitement pour la polykystose rénale (pkrad) de l'adulte Download PDF

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WO2018136933A1
WO2018136933A1 PCT/US2018/014844 US2018014844W WO2018136933A1 WO 2018136933 A1 WO2018136933 A1 WO 2018136933A1 US 2018014844 W US2018014844 W US 2018014844W WO 2018136933 A1 WO2018136933 A1 WO 2018136933A1
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disease
stim1
stiml
kidney disease
sirna
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PCT/US2018/014844
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English (en)
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Liudmila Cebotaru
William B. Guggino
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The Johns Hopkins University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/22—Boron compounds
    • 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

Definitions

  • ADPKD Autosomal dominant polycystic kidney disease
  • ADPKD is one of the most prevalent, potentially lethal, monogenic human disorders, i.e., a disorder caused by a defect or defects in a single gene.
  • ADPKD is associated with large interfamilial and intrafamilial variability, which can be explained, in part, by its genetic heterogeneity and modifier genes.
  • ADPKD also is the most common of the inherited cystic kidney diseases, a group of disorders having related, but distinct pathogenesis, and which are characterized by the development of renal cysts and various extrarenal manifestations.
  • ADPKD Alzheimer's disease
  • these manifestations include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation aneurysms, mitral valve prolapse, and abdominal wall hernias.
  • cysts in other organs such as the liver, seminal vesicles, pancreas, and arachnoid membrane
  • other abnormalities such as intracranial aneurysms and dolichoectasias, aortic root dilatation aneurysms, mitral valve prolapse, and abdominal wall hernias.
  • ADPKD is estimated to affect at least 1 in every 1000 individuals worldwide.
  • the presently disclosed subject matter identifies stromal interaction molecule 1 (STIMl) as a potential therapeutic target for treating diseases or conditions associated with elevated STIMl levels. More particularly, in some aspects, the presently disclosed subject matter demonstrates that inhibition of HDAC6 in combination with inhibition or knock down of STIMl synergistically influences cAMP and Ca 2+ levels in Madin-Darby canine kidney (MDCK) cells. This observation suggests that inhibition of HDAC6 combined with inhibition or knock down of STIMl can be used to treat renal diseases, including renal cystic diseases and polycystic renal diseases, such as autosomal dominant polycystic kidney disease (ADPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • the presently disclosed subject matter provides a method of treating ADPKD in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of an HDAC6 inhibitor in combination with a STIMl inhibitor.
  • inhibition of HDAC6 combined with inhibition or knock down of STIMl can be used to treat cancer.
  • FIG. 1A and FIG. IB show STIMl expression in PN18/PH2 cells.
  • FIG. 1A is a Western blot showing expression of STIMl in PN and PH cells treated with tubacin.
  • FIG. 2A and FIG. 2B show STIMl expression in PN18/PH2 cells treated with tubacin.
  • FIG. 2A is a Western blot showing expression of STIMl in PN and PH cells, as also shown in FIG. 1A.
  • FIG. 3A and FIG. 3B show STIMl knockdown in PN cells using STIMl siRNA.
  • FIG. 3A is a representative Western blot showing expression of STIMl in PN cells transfected with various concentrations of STIMl siRNA or scrambled RNA for 72 hours.
  • FIG. 3B is representative graphs showing Western blotting analyses revealing the downregulation of STIMl expression in PN cells at 72 h after STIMl siRNA (1 nM) transfection. Columns represent averages ⁇ standard errors of the STIMl expression. Data were analyzed by nonparametric t test. Experiment was repeated 4 times. ***P ⁇ 0.001 ;
  • FIG. 4A and FIG. 4B show a. Cyclase 6 (Ac6) expression in PN/STIM1 siRNA cells treated with tubacin.
  • FIG. 4A is a Western blot (left panel) and fold changes relative to PN for STIM1 expression (right panel).
  • FIG. 4B shows fold changes relative to PN for a. cyclase 6;
  • FIG. 5 shows cAMP levels in siRNA-STIMl -PN cells treated with tubacin/forskolin/IBMX/W7.
  • 3 nM siRNA-STIMl (Origene) was used in this experiment to knockdown STIM1.
  • Each set of data is from 3-6 individual wells.
  • PN18 confluent cells were treated with tubacin (10 ⁇ ) for 16h and then treated with forskolin (100 ⁇ ) or 3-isobutyl-l -methylxanthine (IBMX) (100 ⁇ ) for 30 min before harvesting the cells for assay.
  • Cyclic AMP levels were measured with a direct cAMP enzyme immunoassay kit based on the manufacturer's protocol. Results are expressed as pmole/mL. Columns represent averages ⁇ SEs. *P ⁇ 0.05, **** P ⁇ 0.0001.
  • Statistical analysis was performed using a 2-tailed Student t-test. *Compared with PN cells unless indicated with bars;
  • FIG. 6 shows cAMP levels in siRNA-STIMl -PN cells treated with tubacin/W7 (N-(6-Aminohexyl)-5-chloro-l-naphthalenesulfonamide hydrochloride).
  • Tubacin/W7 N-(6-Aminohexyl)-5-chloro-l-naphthalenesulfonamide hydrochloride.
  • Cyclic AMP levels were measured with a direct cAMP enzyme immunoassay kit based on the manufacturer's protocol. Results are expressed as pmole/mL. Columns represent averages ⁇ SEs. *P ⁇ 0.05, ** P ⁇ 0.001 , *** P ⁇ 0.0005.
  • Statistical analysis was performed using a 2-tailed Student t- test;
  • FIG. 7A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, and FIG. 7F show protein expression of STIM1 in ⁇ and PH cells, Pkdl mice.
  • FIG. 8A, FIG. 8B, and FIG. 8C show the effect of STIM siRNA on PN18 cyst size
  • FIG. 9A and FIG. 9B show that Forskolin significantly increased the PN18 cyst, whereas 2-APB, Forskolin+2-APB, STIM1 siRNA, Forskolin +STIM1 siRNA, Tubacin, Forskolin+Tubacin significantly inhibited the cyst growth;
  • FIG. 10A, FIG. 10B, FIG. I OC, FIG. 10D, FIG. 10E, and FIG. 10F demonstrate intracellular Ca 2+ and ATP-induced release in STIM1 siRNA-PN/PH cells treated with tubacin;
  • FIG. 1 1 A, FIG. 1 1B, FIG. 1 1C, FIG. 11D, FIG. HE, and FIG. 11F show intracellular Ca 2+ (F340/F380) levels obtained by ratiometric Fura-2 AM analysis of PN/PH cells treated with Tubacin (10 ⁇ ) for 16h;
  • FIG. 12 A and FIG. 12B show cAMP levels in PN/PH cells treated with STIM1 siRNA and W7;
  • FIG. 13 shows cAMP levels in PN cells treated with 2APB/Forskolin/IBMX
  • FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D, FIG. 14E, and FIG. 14F show the effect of STIM1 siRNA on ac.aTubulin expression in PN cells.
  • FIG. 15 A, FIG. 15B, FIG. 15C, FIG. 15D, FIG. 15E, and FIG. 15F show IP3R type I/II/III expression in PN cells treated with STIMlsiRNA, 2-APB or Tubacin.
  • STIM1 is a transmembrane protein with its Ca 2+ -sensing domain facing the endoplasmic reticulum (ER). When STIM1 senses ER Ca 2+ , it is translocated to the plasma membrane, where it activates store operated Ca 2+ entry (SOCE). STIM1 may be a therapeutic target in diseases with dysregulated calcium flux. Dysregulation of calcium flux has been reported in cancers, autoimmune diseases, and other diseases. Levels of STIMl may be elevated in subjects with autosomal dominant polycystic kidney disease (ADPKD). In some embodiments, reducing the levels of STIMl in subjects may treat (ADPKD). II. HISTONE DEACETYLASE 6 (HDAC6)
  • HDAC6 a member of the HDAC family, is predominantly localized to the cytoplasm and has a unique substrate specificity for the deacetylation of tubulin. Many important biological processes are regulated by HDAC6, including
  • HDAC6 expression and activity are involved in a number of diseases, including cancer. HDAC6 activity is elevated in ADPKD cells, and HDAC6 may play a role in cyst formation in ADPKD.
  • Inhibitors and siRNA may be used to reduce levels or activity of STIMl in subjects in need thereof.
  • the one or more agents capable of inhibiting or knocking down STIMl comprises an siRNA.
  • the siRNA comprises siRNA STIM 1.
  • the one or more agents capable of inhibiting or knocking down STIMl comprises an STIMl inhibitor.
  • Inhibitors and siRNA may be used to reduce levels or activity of STIMl in subjects in need thereof.
  • the one or more agents capable of inhibiting or knocking down STIMl comprises an siRNA.
  • the siRNA comprises siRNA STIM 1.
  • the one or more agents capable of inhibiting or knocking down STIMl comprises an STIMl inhibitor.
  • 2-APB inhibits both IP 3 receptors and TRP channels and is used in research to manipulate intracellular release of calcium ions (Ca 2+ ).
  • 2-APB is a powerful modifier of store-operated calcium channels (SOC) function and causes STIMl clustering in a cell and prevents STIMl from moving toward the plasma membrane.
  • SOC store-operated calcium channels
  • 2-APB is at least as effective, or in other embodiments, is more effective, than siRNA in inhibiting or knocking down STIMl.
  • STIMl inhibitors include ML-9 (l-(5-Chloronaphthalenesulfonyl) homopiperazine hydrochloride) and SKF-96365 (l-[2-(4-Methoxyphenyl)-2-[3-(4- methoxyphenyl)propoxy]ethyl]imidazole, l-[ -(3-(4-Methoxyphenyl)propoxy)-4- methoxyphenethyl]-lH-imidazole hydrochloride), and derivatives thereof.
  • HDAC6i histone deacetylase 6
  • STIMl play a synergistic role in influencing both cyclic adenosine monophosphate (cAMP) and Ca 2+ levels.
  • HDAC6i histone deacetylase 6
  • STIMl knockdown has never been shown to be synergistic with an HDAC6 inhibitor, such as tubacin, in reducing cAMP levels and, accordingly, the therapeutic regime provided herein has not been proposed before.
  • the presently disclosed subject matter demonstrates that histone deacetylase inhibition (HDACi) causes a dramatic drop in resting Ca 2+ and in thapsigargin-induced release of Ca 2+ from the ER.
  • HDACi histone deacetylase inhibition
  • the presently disclosed subject matter further shows that HDACi increases the release of Ca 2+ induced by ATP, mostly likely caused by sustained high levels of STIMl.
  • an HDAC6 inhibitor can increase the steady state levels of STIMl. Knocking down STIMl dramatically reduces the ATP-dependent release of Ca 2+ into the intracellular compartment and the
  • the HDAC6 inhibitor is selected from the group consisting of tubacin (N-(4- ⁇ (2R,4R,6S)-4- ⁇ [(4,5-diphenyl-l,3-oxazol-2- yl)sulfanyl]methyl ⁇ -6-[4-(hydroxymethyl)phenyl]-l,3-dioxan-2-yl ⁇ phenyl)-N'- hydroxyoctanediamide), tubastatin (N-Hydroxy-4-(2-methyl-l ,2,3,4-tetrahydro- pyrido[4,3-b]indol-5-ylmethyl)benzamide hydrochloride; N-Hydroxy-4-((2-methyl- 3,4-dihydro-lH-pyrido[4,3-b]-indol-5(2H)-yl)methyl)benzamide hydrochloride), and derivatives thereof.
  • Representative HDAC6 inhibitors are disclosed in WO2015/06168
  • the disclosed STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions may be used in methods of treatment for diseases.
  • the disclosed STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions may be useful for treating disease of the kidneys in a subject.
  • the methods of treatment may comprise administering a therapeutically effective amount of the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors disclosed herein,
  • STIMl diseases in which STIMl is thought to be involved include, but are not limited to kidney disease, polycystic disease, autosomal dominant polycystic kidney disease, Alzheimer's disease, cancers and cancer-related diseases, including melanoma, glioblastoma, colorectal cancer, neuroblastoma, breast cancer, non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, and renal cell cancer; immune- related diseases, including severe immunodeficiency, Kaposi sarcoma, thalassemia, systemic lupus erreythematous, cerebral vasospasm, Sjogren's syndrome, and multiple schlerosis, and other diseases, such as hypertension, obesity, diabetes, acute lung injury, and sepsis.
  • kidney disease polycystic disease
  • autosomal dominant polycystic kidney disease Alzheimer's disease
  • cancers and cancer-related diseases including melanoma, glioblastoma, colorectal cancer, neuroblast
  • STIMl levels may be increased in subjects with kidney disease, polycystic disease, autosomal dominant polycystic kidney disease,
  • Alzheimer's disease, cancers and cancer-related diseases including melanoma, glioblastoma, colorectal cancer, neuroblastoma, breast cancer, non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, and renal cell cancer; immune- related diseases, including severe immunodeficiency, Kaposi sarcoma, thalassemia, systemic lupus erreythematous, cerebral vasospasm, Sjogren's syndrome, and multiple schlerosis, and other diseases, such as hypertension, obesity, diabetes, acute lung injury, and sepsis.
  • immune- related diseases including severe immunodeficiency, Kaposi sarcoma, thalassemia, systemic lupus erreythematous, cerebral vasospasm, Sjogren's syndrome, and multiple schlerosis, and other diseases, such as hypertension, obesity, diabetes, acute lung injury, and sepsis.
  • the presently disclosed subject matter provides a method for treating a disease or disorder associated with an elevated level of stromal interaction molecule 1 (STIMl), the method comprising administering to a subject in need of treatment thereof a histone deacetylase 6 (HDAC6) inhibitor in combination with one or more agents capable of inhibiting or knocking down STIMl.
  • STIMl stromal interaction molecule 1
  • the inhibitor composition comprises one or more HDAC6 inhibitors and one or more agents capable of inhibiting or knocking down STIMl . i. KIDNEY DISEASE
  • the disease or disorder associated with an elevated level of stromal interaction molecule 1 is a polycystic disease.
  • the polycystic disease comprises a renal cystic disease.
  • the renal cystic disease comprises a polycystic kidney disease.
  • the polycystic kidney disease is selected from the group consisting of an autosomal dominant polycystic kidney disease (ADPKD) and an autosomal recessive kidney disease (ARPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive kidney disease
  • the polycystic kidney disease comprises an autosomal dominant polycystic kidney disease (ADPKD).
  • Kidney disease also known as nephropathy or renal disease, is damage to or disease of a kidney.
  • Nephritis is inflammatory kidney disease.
  • Nephrosis is noninflammatory kidney disease.
  • Kidney disease may cause impaired kidney function.
  • Kidney disease may cause kidney failure.
  • Autosomal dominant polycystic kidney disease is characterized by the progressive enlargement of multiple renal cysts, renal function, resulting in renal failure in 50% of patients. Cysts may develop in every nephron segment through a combination of aberrant epithelial cell proliferation and abnormal fluid secretion.
  • ADPKD may be associated with several abnormalities, including alterations in growth factor receptor distribution and activation, altered extracellular matrix, and mispolarization of essential membrane proteins. Cyst fluid is produced by a cAMP-dependent mechanism similar to that found in secretory epithelia. Misregulation of Ca 2+ may be associated with cyst formation in ADPKD.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to treat autosomal dominant kidney disease. Treating polycystic kidney disease may include, but is not limited to improving renal function, maintaining renal function, preventing renal failure, treating renal failure, reducing the number of renal cysts, and/or reducing the number of renal cysts.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to prevent autosomal dominant polycystic kidney disease.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to treat renal cysts.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to reduce the number of renal cysts.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to reduce the size of renal cysts.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to reduce the number of renal cysts and the size of renal cysts.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may improve renal function.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to treat renal failure.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may be used to prevent renal failure.
  • the STIMl inhibitors, STIMl siRNA, HDAC6 inhibitors, and compositions disclosed herein may reduce the need for kidney transplants in subjects with ADPKD.
  • one or more STIMl inhibitor may be used to treat autosomal dominant polycystic kidney disease.
  • one or more STIMl siRNA may be used to treat autosomal polycystic kidney disease.
  • one or more HDAC6 inhibitors may be used to treat autosomal polycystic kidney disease.
  • one or more STIMl inhibitors and one or more HDAC6 inhibitors may be used to treat autosomal dominant polycystic
  • the presently disclosed subject matter provides a method for inhibiting stromal interaction molecule 1 (STIMl) as a co-treatment for ADPKD.
  • STIMl stromal interaction molecule 1
  • an inhibitor composition to treat autosomal dominant polycystic kidney disease comprises one or more HDAC6 inhibitors and one or more agents capable of inhibiting or knocking down STIMl.
  • Methods of treatment may include any number of modes of administering a disclosed inhibitors, siRNA, and compositions.
  • Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders.
  • the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire®).
  • the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.
  • the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • a physiologically acceptable diluent such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.
  • the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
  • the term “combination” is used in its broadest sense and means that a subject is administered at least two agents. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state.
  • the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days.
  • the active agents are combined and administered in a single dosage form.
  • the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other).
  • the single dosage form may include additional active agents for the treatment of the disease state.
  • compositions can be administered alone or in combination with adjuvants that enhance stability of the agents, facilitate
  • inventions provide increased dissolution or dispersion, increase activity, provide adjuvant therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • the timing of administration of the inhibitors can be varied so long as the beneficial effects of the combination of these agents are achieved. Accordingly, the phrase "in combination with” refers to the administration of at least two inhibitors, and optionally additional agents either simultaneously, sequentially, or a combination thereof. Therefore, a subject administered a combination of at least two inhibitors, and optionally additional agents can receive at least two inhibitors, and optionally additional agents at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of all agents is achieved in the subject.
  • agents administered sequentially can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1 , 2, 3, 4, 5, 10, 15, 20 or more days of one another. Where the agents are administered simultaneously, they can be administered to the subj ect as separate pharmaceutical compositions, each comprising either at least one inhibitor, and optionally additional agents, or they can be administered to a subject as a single pharmaceutical composition comprising all agents.
  • the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent.
  • the effects of multiple agents may, but need not be, additive or synergistic.
  • the agents may be administered multiple times.
  • the two or more agents when administered in combination, can have a synergistic effect.
  • SIGENT “synergistic,” “synergistically” and derivations thereof, such as in a “synergistic effect” or a “synergistic combination” or a “synergistic composition” refer to circumstances under which the biological activity of a combination of an agent and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually.
  • Synergy can be expressed in terms of a "Synergy Index (SI),” which generally can be determined by the method described by F. C. Kull et al. Applied Microbiology 9, 538 (1961), from the ratio determined by:
  • Q A is the concentration of a component A, acting alone, which produced an end point in relation to component A;
  • Q a is the concentration of component A, in a mixture, which produced an end point
  • Q B is the concentration of a component B, acting alone, which produced an end point in relation to component B;
  • Qb is the concentration of component B, in a mixture, which produced an end point.
  • a "synergistic combination” has an activity higher that what can be expected based on the observed activities of the individual components when used alone.
  • a “synergistically effective amount" of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition.
  • the disclosed inhibitors and siRNA may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human).
  • the pharmaceutical compositions may include a "therapeutically effective amount” or a “prophylactically effective amount” of the agent.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • a therapeutically effective amount of the disclosed compositions may be, but is not limited to, about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about 550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about 450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about 350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about 250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about 150 mg/kg, and about 90 mg/kg to about 100
  • compositions may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eyedrop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration.
  • Techniques and formulations may generally be found in "Remington's Pharmaceutical Sciences", (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.
  • compositions are administered and the form of the composition will dictate the type of carrier to be used.
  • the composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration
  • systemic administration e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral
  • topical administration e.g., topical administration
  • Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.
  • Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol.
  • the amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.
  • Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma.
  • the amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.
  • Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose,
  • methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose are examples of binder(s) in a systemic composition.
  • the amount of binder(s) in a systemic composition is typically about 5 to about 50%.
  • Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of
  • disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.
  • Suitable colorants include a colorant such as an FD&C dye.
  • the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.
  • Suitable flavors include menthol, peppermint, and fruit flavors.
  • the amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.
  • Suitable sweeteners include aspartame and saccharin.
  • the amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.
  • Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxy toluene (“BHT”), and vitamin E.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxy toluene
  • the amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.
  • Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate.
  • the amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.
  • Suitable glidants include silicon dioxide.
  • the amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.
  • Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions.
  • the amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.
  • Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate.
  • the amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.
  • Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware.
  • Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239.
  • the amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.
  • systemic compositions include 0.01% to 50% of active and 50% to 99.99% of one or more carriers.
  • Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.
  • Compositions for oral administration can have various dosage forms.
  • the oral dosage form may be a vaccination.
  • the oral dosage form may be solid forms including tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives.
  • the oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.
  • Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film- coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders,
  • disintegrants include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.
  • Specific binders include starch, gelatin, and sucrose.
  • Specific disintegrants include alginic acid and croscarmelose.
  • Specific lubricants include magnesium stearate, stearic acid, and talc.
  • Specific colorants are the FD&C dyes, which can be added for appearance.
  • Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.
  • Capsules typically include an active compound, and a carrier including one or more diluents disclosed above in a capsule comprising gelatin.
  • Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics.
  • Implants can be of the biodegradable or the non-biodegradable type.
  • ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.
  • Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action.
  • the coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.
  • compositions for oral administration can have liquid forms.
  • suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non- effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like.
  • Liquid compositions which may be administered orally, may include a disclosed immunogenic proteins, compositions, and vaccines and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants.
  • Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose.
  • Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.
  • compositions may be topically administered.
  • Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse- out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.
  • the carrier of the topical composition preferably aids penetration of the compounds into the skin.
  • the carrier may further include one or more optional components.
  • Transdermal administration may be used to facilitate delivery.
  • a carrier may include a single ingredient or a combination of two or more ingredients.
  • the carrier includes a topical carrier.
  • Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.
  • the carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.
  • Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1 , 3 -diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral
  • Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.
  • the amount of propellant(s) in a topical composition is typically about 0% to about 95%.
  • Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof.
  • Specific solvents include ethyl alcohol and homotopic alcohols.
  • the amount of solvent(s) in a topical composition is typically about 0% to about 95%.
  • Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5- carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.
  • the amount of thickener(s) in a topical composition is typically about 0% to about 95%.
  • Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified
  • Montmorillonite clay hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof.
  • the amount of powder(s) in a topical composition is typically 0% to 95%.
  • the amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.
  • Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.
  • compositions can be manufactured in a manner known in the art, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the presently disclosed pharmaceutical compositions can be administered by rechargeable or biodegradable devices.
  • a variety of slow-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinacious biopharmaceuticals.
  • Suitable examples of sustained release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. , films or microcapsules.
  • Sustained release matrices include polyesters, hydrogels, polylactides (U.S. Patent No.
  • Sustained release compositions also include liposomally entrapped compositions comprising at least one inhibitor which can be prepared by methods known in the art (Epstein et al. (1985) Proc. Natl. Acad. Sci. U.S.A. 82:3688; Hwang et al. (1980) Proc. Natl. Acad. Sci. U.S.A. 77:4030; U. S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324A).
  • the liposomes are of the small (about 200-800 angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.
  • Such materials can comprise an implant, for example, for sustained release of the presently disclosed compositions, which, in some
  • inventions can be implanted at a particular, pre-determined target site.
  • compositions for parenteral administration include aqueous solutions of compositions comprising, for example, at least two inhibitors.
  • the presently disclosed pharmaceutical compositions can be formulated in aqueous solutions, for example, in some embodiments, in physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiologically buffered saline.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiologically buffered saline.
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • suspensions of compositions include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compositions comprising, for example, at least one two inhibitors to allow for the preparation of highly concentrated solutions.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, preservatives, buffering agents, and the like can be present.
  • the pH of the presently disclosed topical composition can be adjusted to a physiologically acceptable range of from about 6.0 to about 9.0 by adding buffering agents thereto such that the composition is physiologically compatible with a subject's skin.
  • compositions are formulated into pharmaceutically acceptable dosage forms, such as described herein or by other conventional methods known to those of skill in the art.
  • the "effective amount” or “therapeutically effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response.
  • the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the encapsulating matrix, the target tissue, and the like.
  • compositions can be administered to a subject for therapy by any suitable route of administration, including orally, nasally, transmucosally, ocularly, rectally, intravaginally, parenterally, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra-stemal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections, intracisternally, topically, as by powders, ointments or drops (including eyedrops), including buccally and sublingually, transdermally, through an inhalation spray, or other modes of delivery known in the art.
  • suitable route of administration including orally, nasally, transmucosally, ocularly, rectally, intravaginally, parenterally, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intra
  • compositions e.g., comprising at least two inhibitors, such that it enters the patient's system and, thus, are subject to metabolism and other like processes, for example, subcutaneous administration.
  • parenteral administration and “administered parenterally” as used herein mean modes of administration other than enteral and topical
  • administration usually by injection, and includes, without limitation, intravenous, intramuscular, intarterial, intrathecal, intracapsular, intraorbital, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • the presently disclosed subject matter provides a pharmaceutical composition including at least two inhibitors, and optionally additional agents, alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient.
  • the presently disclosed subject matter provides a pharmaceutical composition comprising at least two inhibitors, and optionally additional agents, and a pharmaceutically acceptable carrier.
  • the compounds of the disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams and Wilkins (2000).
  • compositions of the present disclosure in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using
  • Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.
  • the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.
  • compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier, a therapeutically effective amount of a histone deacetylase 6 (HDAC6) inhibitor, and one or more agents capable of inhibiting or knocking down STIM1.
  • HDAC6 histone deacetylase 6
  • the one or more agents capable of inhibiting or knocking down STIM1 in the pharmaceutical composition is an siRNA.
  • the one or more agents capable of inhibiting or knocking down STIMlin the pharmaceutical composition is selected from ML-9 (1 - (5-Chloronaphthalenesulfonyl) homopiperazine hydrochloride), SKF-96365 (l -[2-(4- Methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl]imidazole, 1-[ ⁇ -(3-(4- Methoxyphenyl)propoxy)-4-methoxyphenethyl]-lH-imidazole hydrochloride), and derivatives thereof.
  • composition is selected from: tubacin, tubastatin, and derivatives thereof.
  • the inhibitors, siRNA, and compositions disclosed herein may be included in kits comprising the inhibitors, siRNA, and/or compositions; and information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans).
  • the kit may include an additional pharmaceutical composition for use in combination therapy.
  • the kit may include buffers, reagents, or other components to facilitate the mode of administration.
  • the kit may include materials to facilitate oral administration.
  • the kit may include materials to facilitate nasal mucousal administration.
  • the kit may include materials that facilitate sublingual administration.
  • the information and instructions may be in the form of words, pictures, or both, and the like.
  • the kit may include the medicament, a composition, or both; and information, instructions, or both, regarding methods of application of medicament, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).
  • the modifier "about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
  • the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4" also discloses the range “from 2 to 4.”
  • the term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 1 1 %, and “about 1 " may mean from 0.9-1.1. Other meanings of "about” may be apparent from the context, such as rounding off, so, for example "about 1 " may also mean from 0.5 to 1.4.
  • the term "about,” when referring to a value can be meant to encompass variations of, in some embodiments, ⁇ 100% in some embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • compositions disclosed herein may be administered in various routes including, but not limited to, oral, mucosal, mucosal nasal, parenteral (including intravenous, intra-arterial, and other appropriate parenteral routes), intrathecally, intramuscularly, subcutaneously, colonically, rectally, and nasally, transcutaneously, among others.
  • parenteral including intravenous, intra-arterial, and other appropriate parenteral routes
  • intrathecally intramuscularly, subcutaneously, colonically, rectally, and nasally, transcutaneously, among others.
  • the dosing of the compositions described herein to obtain a therapeutic or prophylactic effect may be determined by the circumstances of the subject, as known in the art.
  • the dosing of a subject herein may be accomplished through individual or unit doses of the compositions described herein or by a combined or prepackaged or pre-formulated dose of the compositions described herein.
  • Administration may depend upon the amount of the compositions described herein administered, the number of doses, and duration of treatment. For example, multiple doses of the compositions described herein may be administered.
  • the frequency of administration of the compositions described herein may vary depending on any of a variety of factors.
  • the duration of administration of the compositions described herein e.g., the period of time over which the compositions described herein are administered, may vary, depending on any of a variety of factors, including subject response, etc.
  • the amount of the disclosed compositions administered may vary according to factors such as the degree of susceptibility of the individual, the age, sex, and weight of the individual, idiosyncratic responses of the individual, the dosimetry, and the like. Detectably effective amounts of the disclosed compositions of the present disclosure may also vary.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • a “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” or “pharmaceutically acceptable adjuvant” means an excipient, diluent, carrier, and/or adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use and/or human pharmaceutical use.
  • “A pharmaceutically acceptable excipient, diluent, carrier and/or adjuvant” as used herein includes one or more such excipients, diluents, carriers, and adjuvants.
  • a “subject” and “patient” are used interchangeably herein.
  • the subject treated by the presently disclosed methods, uses, inhibitors, and compositions comprising those inhibitors in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject.”
  • a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes.
  • Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like.
  • mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; cap
  • an animal may be a transgenic animal.
  • the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects.
  • a "subject" can include a patient afflicted with or suspected of being afflicted with a condition or disease.
  • the subject is a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, avian, or amphibian.
  • the subject is a human.
  • a therapeutically effective amount of a compound may include the amount necessary to provide a therapeutically effective result in vivo.
  • the amount of the compound or composition must be effective to achieve a response, including but not limited to a total prevention of (e.g., protection against) of a condition, improved survival rate or more rapid recovery, improvement or elimination of symptoms associated with the condition (such as cancer), or other indicators as are selected as appropriate measures by those skilled in the art.
  • a suitable single dose size includes a dose that is capable of preventing or alleviating (reducing or eliminating) a symptom in a subject when administered one or more times over a suitable time period.
  • the "therapeutically effective amount" of a compound or composition as described herein may depend on the route of administration, type of subject being treated, and the physical characteristics of the subject. These factors and their relationship to dose are well known to one of skill in the medicinal art, unless otherwise indicated.
  • treat refers to acting upon a condition with an agent to affect the condition by improving or altering it.
  • the condition includes, but is not limited to conditions in which STIM1 is involved in the pathophysiology, such as kidney disease.
  • the aforementioned terms cover one or more treatments of a condition in a subject (e.g., a mammal, typically a human or non-human animal of veterinary interest), and include: (a) reducing the risk of occurrence of the condition in a subject determined to be predisposed to the condition but not yet diagnosed, (b) impeding the development of the condition, and/or (c) relieving the condition, e.g., causing regression of the condition and/or relieving one or more condition symptoms.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • compositions and methods will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
  • STIM1 expression in PN18/ PH2 cells treated with tubacin was measured. These data indicate that protein expression of STIM1 is significantly increased in PN cells compared with PH cells. Further, these data show that the HDAC6 inhibitor, tubacin, has no effect on STIM 1 expression.
  • STIM1 expression in PN18/ PH2 cells treated with tubacin was again measured. Consistent with the data shown in FIG. 1A and FIG. IB, the HDAC6 inhibitor, tubacin, has no effect on STIM1 expression.
  • FIG. 3A and FIG. 3B show STIM1 knockdown in PN cells using STIM1 siRNA.
  • PN cells were cultured as mentioned in culture methods.
  • Mouse STIM1 siRNA or Scramble siRNA was transfected according to the manufacturer's instructions.
  • FIG. 3A is a representative Western blot showing expression of STIM1 in PN cells transfected with various concentrations of STIM1 siRNA or scrambled RNA for 72h.
  • FIG. 3B is representative graphs showing Western blotting analyses revealing the downregulation of STIM1 expression in PN cells at 72 h after STIM1 siRNA (InM) transfection. These data show that protein expression of STIM1 is significantly decreased in PN cells compared with PH cells after treatment with siRNA STIM 1.
  • FIG. 4A and FIG. 4B show a. cyclase 6 expression in PN/STIM1 siRNA cells treated with tubacin. These data indicate that protein expression of Ad. Cyclase 6 is significantly decreased in PN cells after treatment with STIM1 siRNA or in combination with tubacin compared with control PN cells.
  • siRNA-STIMl-PN cells treated with Tubacin/Forskolin/IBMX/W7 3nM siRNA-STIMl(Origene) was used in this experiment to knockdown STIM1.
  • Each set of data is from 3-6 individual wells.
  • PN18 confluent cells were treated with tubacin (10 ⁇ ) for 16h and then treated with Forskolin (100 ⁇ ) or IBMX (100 ⁇ ) for 30 min before harvesting the cells for assay. Cyclic AMP levels were measured with a direct cAMP Enzyme immunoassay Kit based on the manufacturer's protocol. Results are expressed as pmole/mL.
  • FIG. 6 shows cAMP levels in siRNA-STIMl -PN cells treated with
  • Tubacin/W7 Each set of data is from 3-6 individual wells. PN18 confluent cells were treated with tubacin (10 ⁇ ) or W7 (50 ⁇ ) for 16h. Cyclic AMP levels were measured with a direct cAMP. Enzyme immunoassay Kit based on the
  • FIG. 7 A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, and FIG. 7F show protein expression of STIMl in PN and PH cells, Pkdl mice.
  • Pkdl null (PN) and heterozygous (PH) cells were grown in 10-cm culture dishes at permissive conditions (33 °C) with ⁇ -interferon in culture media. Cells were then transferred to non-permissive conditions at 37 °C, in ⁇ -interferon free culture media, and evaluated at full confluency. At day five, cells were harvested for Western blot assay.
  • FIG. 7 A, FIG. 7B, FIG. 7C, FIG. 7D, FIG. 7E, and FIG. 7F show protein expression of STIMl in PN and PH cells, Pkdl mice.
  • PN Pkdl null
  • PH heterozygous
  • FIG. 7 A is a Western blot showing expression of STIMl in PN and PH cells.
  • FIG. 7B the columns represent averages ⁇ standard errors of the STIMl expression in PN and PH cells. ****P ⁇ 0.0001. Data were analyzed by nonparametric t-test. The experiment was repeated 6 times. These data indicate that protein expression of STIMl is significantly increased in PN cells compared to PH cells. Protein expression of STIMl also is significantly increased in induced Pkdl mice.
  • cysts were treated with Control (opti-MEM), transfection reagent control, siRNA control, STIMl siRNA
  • Forskolin +STIM1 siRNA Tubacin. Forskolin+Tubacin
  • 2-APB, Forskolin+2-APB, STIMl siRNA, Forskolin +STIM1 siRNA, Tubacin, Forskolin+Tubacin significantly inhibited the cyst growth.
  • FIG. 10A, FIG. 10B, and FIG. IOC demonstrate intracellular Ca 2+ and ATP- induced release in STIMlsiRNA-PN/PH cells treated with tubacin.
  • FIG. 10A shows representative traces of intracellular Ca 2+ release in response to 100 ⁇ ATP in STIMl siRNA-PN/PH cells treated with tubacin.
  • FIG. 1 OB is a graph summarizing the average amplitude of Ca 2+ release in response to ATP.
  • FIG. 11 A, FIG. 1 IB, FIG. 11C, FIG. 1 ID, FIG. HE, and FIG. 1 IF show intracellular Ca 2+ (F340/F380) levels obtained by ratiometric Fura-2 AM analysis of PN/PH cells treated with Tubacin (10 ⁇ ) for 16h.
  • FIG. 11A shows representative traces of intracellular Ca 2+ release in response to Thapsigargin (4 ⁇ ) in PN/PH cells treated with tubacin.
  • cAMP levels in PN/PH cells treated with STIMl siRNA and W7 are shown.
  • Pkdl null (PN) cells were grown in 10-cm culture dishes at permissive conditions (33 °C) with ⁇ -interferon in culture media. Cells were then transferred to non-permissive conditions at 37 °C, ⁇ -interferon free culture media.
  • mouse STIMl siRNA (3 nM) was transfected using Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer's instructions and evaluated at full confluency.
  • FIG. 13 shows cAMP levels in PN cells treated with 2-APB/Forskolin/IBMX.
  • PN18 confluent cells were treated with 2-APB (10 ⁇ ) for 16 and then treated with Forscolin (100 ⁇ ) or IB MX (100 ⁇ ) for 30 min. before harvesting the cells for assay. Cyclic AMP levels were measured with a direct cAMP Enzyme immunoassay Kit based on the manufacturer's protocol. Results are expressed as pmole/ml.
  • FIG. 14A and FIG. 14B show the effect of STIM1 siRNA on ac.aTubulin expression in PN cells.
  • Pkdl null (PN) cells were grown in 10-cm culture dishes at permissive conditions (33 °C) with ⁇ -interferon in culture media. Cells were then transferred to non-permissive conditions at 37 °C, ⁇ -interferon free culture media.
  • mouse STIM1 siRNA (3 nM) was transfected using
  • Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer's instructions and evaluated at full confluency. At day five, cells were harvested for WB
  • FIG. 14A is a Western blot showing expression of ac.aTubulin in PN and PN/S cells.
  • FIG. 14B columns represent averages ⁇ standard errors of the ac.aTubulin expression. Experiment was repeated for four times at least. *P ⁇ 0.05. Data were analyzed by nonparametric t test. Experiment was repeated 6 times.
  • IP3R type I/II/III Expression in PN Cells Treated with STIMl siRNA 2-APB or Tubacin
  • FIG. 15 A, FIG. 15B, FIG. 15C, FIG. 15D, FIG. 15E, and FIG. 15F show IP3R type I/II/III expression in PN cells treated with STIMl siRNA, 2-APB or Tubacin. These data demonstrate that the total protein expression of IP3 receptors is significantly downregulated in PN cells treated with 2-APB and Tubacin compared with the control PN cells. The binding of IP3 receptors to PC2 is increased in cells treated with 2-APB and Tubacin.
  • STIM1 is a Ca 2+ sensor that activates CRAC channels and migrates from the Ca 2+ store to the plasma membrane, Nature, 437, 902-905 (2005);
  • a method for treating a disease or disorder associated with an elevated level of stromal interaction molecule 1 comprising administering to a subject in need of treatment thereof one or more agents capable of inhibiting or knocking down STIM1.
  • Clause 2 The method of clause 1, wherein the one or more agents capable of inhibiting or knocking down STIM1 comprises an siRNA.
  • Clause 3 The method of clause 1, wherein the one or more agents capable of inhibiting or knocking down STIMlis 2-ABP.
  • Clause 4 The method of clause 1, wherein the disease or disorder associated with an elevated level of stromal interaction molecule 1 (STIM1) is a polycystic disease.
  • STIM1 stromal interaction molecule 1
  • Clause 5 The method of clause 4, wherein the polycystic disease is a renal cystic disease. Clause 6. The method of clause 5, wherein the renal cystic disease is a polycystic kidney disease.
  • polycystic kidney disease is selected from autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive kidney disease (ARPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive kidney disease
  • the disease or disorder associated with an elevated level of stromal interaction molecule 1 is selected from: Alzheimer's disease; cancers and cancer-related diseases, including melanoma, glioblastoma, colorectal cancer, neuroblastoma, breast cancer, non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, and renal cell cancer; immune-related diseases, including severe immunodeficiency, Kaposi sarcoma, thalassemia, systemic lupus erreythematous, cerebral vasospasm, Sjogren's syndrome, multiple schlerosis, hypertension, obesity, diabetes, acute lung injury, and sepsis.
  • STIM1 stromal interaction molecule 1
  • a method for treating a disease or disorder associated with an elevated level of stromal interaction molecule 1 comprising administering to a subject in need of treatment thereof a histone deacetylase 6 (HDAC6) inhibitor in combination with one or more agents capable of inhibiting or knocking down STIM1.
  • HDAC6 histone deacetylase 6
  • Clause 11 The method of clause 10, wherein the one or more agents capable of inhibiting or knocking down STIM1 is an siRNA.
  • Clause 12 The method of clause 10, wherein the one or more agents capable of inhibiting or knocking down STIMlis 2-ABP.
  • Clause 14 The method of clause 10, wherein the disease or disorder associated with an elevated level of stromal interaction molecule 1 (STIM1) is a polycystic disease.
  • STIM1 stromal interaction molecule 1
  • Clause 15 The method of clause 14, wherein the polycystic disease is renal cystic disease.
  • Clause 16 The method of clause 15, wherein the renal cystic disease is polycystic kidney disease.
  • the polycystic kidney disease is selected from autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive kidney disease (ARPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive kidney disease
  • the disease or disorder associated with an elevated level of stromal interaction molecule 1 is selected from: Alzheimer's disease; cancers and cancer-related diseases, including melanoma, glioblastoma, colorectal cancer, neuroblastoma, breast cancer, non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, and renal cell cancer; immune-related diseases, including severe immunodeficiency, Kaposi sarcoma, thalassemia, systemic lupus erreythematous, cerebral vasospasm, Sjogren's syndrome, multiple schlerosis, hypertension, obesity, diabetes, acute lung injury, and sepsis.
  • STIM1 stromal interaction molecule 1
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, a therapeutically effective amount of a histone deacetylase 6 (HDAC6) inhibitor, and one or more agents capable of inhibiting or knocking down STIM1.
  • HDAC6 histone deacetylase 6
  • Clause 21 The pharmaceutical composition of clause 20, wherein the one or more agents capable of inhibiting or knocking down STIM1 is an siRNA.
  • Clause 22 The pharmaceutical composition of clause 20, wherein the one or more agents capable of inhibiting or knocking down STIMlis 2-ABP.

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Abstract

La molécule d'interaction stromale 1 (STIM1) est identifiée comme une cible thérapeutique potentielle pour traiter des maladies ou des affections associées à des teneurs élevées en STIM1. L'inhibition de HDAC6 en combinaison avec l'inhibition ou le knock-down de STIM1 s'est révélée influencer de manière synergique les niveaux d'AMPc et de Ca2+ dans des cellules rénales canines de Madin-Darby (MDCK), suggérant que l'inhibition de HDAC6 combinée à l'inhibition ou le knock-down de STIM1 peut être utilisée pour traiter des maladies rénales, notamment des maladies rénales kystiques et des maladies rénales polykystiques, telles que la polykystose rénale autosomique dominante (PKRAD), ou des cancers.
PCT/US2018/014844 2017-01-23 2018-01-23 Inhibition de la molécule d'interaction stromale 1 (stim1) en tant que co-traitement pour la polykystose rénale (pkrad) de l'adulte WO2018136933A1 (fr)

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CN107475299A (zh) * 2017-09-13 2017-12-15 信雅生物科技（苏州）有限公司 研究stim1基因在非小细胞肺癌中发挥作用的方法及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107475299A (zh) * 2017-09-13 2017-12-15 信雅生物科技（苏州）有限公司 研究stim1基因在非小细胞肺癌中发挥作用的方法及其应用

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