WO2018078922A1 - Preventive agent and therapeutic agent for cataracts, and use of hat inhibitor for production thereof - Google Patents

Preventive agent and therapeutic agent for cataracts, and use of hat inhibitor for production thereof Download PDF

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WO2018078922A1
WO2018078922A1 PCT/JP2017/019034 JP2017019034W WO2018078922A1 WO 2018078922 A1 WO2018078922 A1 WO 2018078922A1 JP 2017019034 W JP2017019034 W JP 2017019034W WO 2018078922 A1 WO2018078922 A1 WO 2018078922A1
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cataract
hat
lens
medium
inhibitor
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PCT/JP2017/019034
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French (fr)
Japanese (ja)
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昌也 沖
文人 金田
佳弘 ▲高▼村
誠司 三宅
博之 内田
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国立大学法人福井大学
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Priority to JP2018547203A priority Critical patent/JP7033317B2/en
Priority to PCT/JP2017/034204 priority patent/WO2018079149A1/en
Publication of WO2018078922A1 publication Critical patent/WO2018078922A1/en

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    • 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
    • A61K31/415—1,2-Diazoles
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    • A61K31/415—1,2-Diazoles
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts

Definitions

  • the present invention relates to a preventive agent, a therapeutic agent for cataract, and use of a HAT inhibitor for producing them. More specifically, the present invention relates to a preventive or therapeutic agent for cataract containing a HAT inhibitor as an active ingredient.
  • Cataract is a disease in which a reduction in visual acuity is caused by turbidity of the lens.
  • a lens affected by cataract develops cloudiness in the nucleus, cortex or posterior capsule.
  • Types of cataracts include age-related cataracts and diabetic cataracts.
  • age-related cataract which has the highest number of affected individuals, has an increased prevalence rate with age, and including the initial opacity, the prevalence rate in the 60s in Japan is 66-85%, in the 70s The prevalence rate is 84-97%, reaching 100% for people over 80 years old.
  • diabetic cataract is a disease that has many affected people under 60 years old and can develop even in young people.
  • Non-Patent Document 1 reports glutathione
  • Non-Patent Document 2 reports pirenoxine.
  • the present invention has been made in view of the above-mentioned conventional problems, and an object thereof is to provide a novel cataract preventive agent, therapeutic agent, and use of a HAT inhibitor for producing them.
  • the present inventors have found that a HAT inhibitor can prevent and treat cataract, and have completed the present invention. That is, the present invention has the following configuration.
  • a preventive or therapeutic agent for cataract which contains a HAT inhibitor as an active ingredient.
  • the HAT inhibitor is selected from the group consisting of HAT1, NAA60, GCN5, PCAF, TIP60, MOZ, MORF, HBO1, MOF, P300, CBP, TAF1, TIFIIIC90, SRC1, SCR3, P600, CLOCK and NAT10.
  • the prophylactic or therapeutic agent for cataract according to ⁇ 1> which targets at least one kind of substance.
  • the HAT inhibitor is a compound derived from polyphenol, a compound containing a heterocycle in the structure, a benzoic acid derivative, or an ⁇ - ⁇ unsaturated carbonyl compound, according to ⁇ 1> or ⁇ 2> A preventive or therapeutic agent for cataracts.
  • HAT inhibitors include curcumin, 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, Epigenetic Multiple Ligand, garcinol, anacardic acid, MG149, C646, NU9056, CPTH2 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone, butyrolactone 3, gallic acid, ( ⁇ )-epigallocatechin gallate, EML425, L002, ISOX DUAL, plumbagin, TH1834, SPV106, One or more compounds selected from the group consisting of Windorphen, ketomin, Remodelin, Embelin, Ischemin, CBP30 and KG501, or a derivative or salt of the compound Prophylactic or therapeutic agents of cataracts according to ⁇ 1> or ⁇ 2>.
  • ⁇ 5> The preventive or therapeutic agent for cataract according to any one of ⁇ 1> to ⁇ 4>, wherein the dosage form is an eye drop.
  • ⁇ 6> The preventive or therapeutic agent for cataract according to any one of ⁇ 1> to ⁇ 5>, wherein the cataract is diabetic cataract.
  • a novel preventive or therapeutic agent for cataract is provided.
  • A It is a model figure showing the example of an action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention.
  • B It is a model figure showing the example of the other action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention.
  • C It is a model figure showing the example of the further another action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention.
  • A A photograph showing the preventive effect of 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane on cataract.
  • B It is a photograph which shows the prevention effect of the cataract by CTK7A.
  • A It is a photograph which shows the prevention effect of the cataract by ISOX DUAL.
  • B It is a photograph which shows the prevention effect of the cataract by a plum baggin.
  • C It is a photograph which shows the prevention effect of the cataract by TH1834.
  • D It is a photograph which shows the prevention effect of the cataract by SPV106.
  • E It is a photograph which shows the prevention effect of the cataract by Windorphen.
  • A It is a photograph which shows the prevention effect of the cataract by Remodelin.
  • B It is a photograph which shows the prevention effect of the cataract by an embelline.
  • C It is a photograph which shows the prevention effect of the cataract by EML425.
  • (D) It is a photograph which shows the prevention effect of the cataract by CBP30.
  • (E) It is a photograph which shows the promotion effect of the cataract by TSA. It is the graph which quantified promotion of lens white turbidity by a HDAC inhibitor, and suppression of lens white turbidity by a HAT inhibitor. It is a photograph which shows the cataract treatment effect by a HAT inhibitor (C646).
  • (A) It is a photograph which shows the cataract treatment effect by the combination of CBP30 and CPTH2.
  • (B) A photograph showing a slice of the lens 4 days after administration of the combination of CBP30 and CPTH2.
  • (A) It is a photograph which shows the cataract treatment effect by CBP30.
  • Cataract refers to any disease that causes opacity in the lens.
  • the opacity that occurs in the lens due to cataract includes, for example, cortical turbidity, nuclear turbidity, posterior subcapsular turbidity, cortical spoke turbidity, anterior capsular turbidity, fibrous folds, water space, transilluminated spot-like turbidity around the nucleus, blisters, There are types such as punctate turbidity and turbidity on the crown.
  • the term “cataract” in this specification is intended to refer to diseases that collectively refer to disease types such as diabetic cataract, congenital cataract, traumatic cataract, atopic cataract, radiation cataract, and steroid cataract. To do.
  • diabetes cataract refers to opacity of the lens that occurs in a patient suffering from a disease that is characterized by a continuously rising glucose concentration in blood or plasma.
  • the disease is hyperglycemia or diabetes.
  • the diabetes is type 1 diabetes or type 2 diabetes.
  • turbidity it is known in large-scale epidemiological studies that turbidity often occurs in the cortex or posterior capsule of the lens. However, the location where turbidity occurs is not limited thereto.
  • the cataract preventive or therapeutic agent according to an embodiment of the present invention is preferably used for the purpose of preventing or treating diabetic cataract.
  • the “prophylactic agent” intends an agent that provides a preventive effect.
  • the preventive effect is intended to be the effect exemplified below, but is not limited thereto.
  • the one or more symptoms related to the disease may be systemic or local.
  • therapeutic agent intends an agent that provides a therapeutic effect.
  • the therapeutic effect is intended to be the effect exemplified below, but is not limited thereto.
  • (1) Reduce the severity of one or more symptoms associated with the disease as compared to when no therapeutic agent is administered.
  • (2) Preventing an increase in the severity or progression of one or more symptoms associated with a disease compared to when no therapeutic agent is administered.
  • (3) Reduce the rate of increase or progression of the severity of one or more symptoms associated with the disease, compared to when no therapeutic agent is administered.
  • the one or more symptoms related to the disease may be systemic or local.
  • HAT inhibitor One embodiment of the present invention contains a HAT inhibitor as an active ingredient.
  • a HAT inhibitor intends the substance which inhibits the function of histone acetylase (Histone Acetyl Transferase: HAT).
  • HAT replaces the amino group of a specific lysine residue contained in histone with an acetyl group. As a result, the chromatin structure formed by DNA and histone is partially loosened, and the gene in the vicinity of the site where histone is acetylated is easily expressed.
  • a HAT inhibitor causes a result of suppressing the expression of a specific gene by inhibiting the above-described process. Therefore, the preventive or therapeutic agent for cataract according to one embodiment of the present invention acts on epigenetic gene expression control.
  • HAT whose function is inhibited by a specific HAT inhibitor is referred to as a “target” of the HAT inhibitor.
  • a HAT inhibitor may “directly” inhibit HAT function, such as by binding to a target HAT.
  • the HAT inhibitor may inhibit the function of HAT "indirectly” by capturing a substance necessary for the function of HAT (in this case, the substance necessary for the function of HAT is also Like the above HAT, it is called “target of HAT inhibitor”). That is, the target of the HAT inhibitor may be HAT or not HAT.
  • the HAT targeted by the HAT inhibitor may be one or more subtypes of HAT among the HAT groups listed in the table below. In one embodiment, the HAT targeted by the HAT inhibitor may be a HAT group belonging to one or more families among the HAT groups described in Table 1 below.
  • the substance targeted by the HAT inhibitor may be NAT10 or BRD4.
  • the target of the HAT inhibitor is selected from substances described herein that can be a target of a HAT inhibitor, and substances recognized by those skilled in the art as a target of a HAT inhibitor. More than types. That is, the target of the HAT inhibitor may be only one type or two or more types. In addition, the HAT inhibitor may target both a substance that is HAT and a substance other than HAT. Furthermore, the target of the HAT inhibitor may be a complex containing the substances described above.
  • the HAT inhibitor is curcumin.
  • the above IUPAC name of curcumin is (1E, 6E) -1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione, CAS number is 458-37-7, structural formula Is the following formula 1.
  • the curcumin targets the P300 / CBP family HAT.
  • the HAT inhibitor is 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane (also known as HAT inhibitor II).
  • the IUPAC name of 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexan, CAS number is 932749- 62-7, the structural formula is the following formula 2.
  • the 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane targets the P300 / CBP family HAT.
  • the HAT inhibitor is CTK7A (also known as HAT inhibitor VII).
  • CTK7A also known as HAT inhibitor VII.
  • the IUPAC name of the above CTK7A is Sodium-4- (3,5-bis (4-hydroxy-3-methoxystyryl) -1H-pyrazol-1-yl) benzoate, CAS number is 1,297262-16-8, and the structural formula is 3.
  • the CTK7A targets P300 and PCAF.
  • the HAT inhibitor is Epigenetic Multiple.
  • Ligand The IUPAC name of Epigenetic Multiple Ligand is 3,5-bis (3,5-Dibromo-4-hydroxybenzylidene) -tetrahydro-2H-pyran-4-one, CAS number is 1020399-52-3, and the structural formula is It is.
  • the Epigenetic Multiple Ligand targets P300.
  • the HAT inhibitor is garcinol.
  • the IUPAC name of the above garcinol is 3-[(3,4-Dihydroxyphenyl) -hydroxymethylidene] -6,6-dimethyl-5,7-bis (3-methylbut-2-enyl) -1- (5-methyl-2- prop-1-en-2-ylhex-4-enyl) bicyclo [3.3.1] nonane-2,4,9-trione, CAS number is 78824-30-3, structural formula is the following formula 5.
  • the garcinol targets P300 and PCAF.
  • the HAT inhibitor is anacardic acid.
  • the IUPAC name of the anacardic acid is 2-hydroxy-6-[(8Z, 11Z) -pentadeca-8,11,14-trienyl] benzoic acid, the CAS number is 11034-77-8, and the structural formula is .
  • the anacardic acid targets P300 and PCAF.
  • the HAT inhibitor is MG149.
  • the IUPAC name of MG149 is 2- (4-heptylphenethyl) -6-hydroxybenzoic acid, the CAS number is 1243583-85-8, and the structural formula is Formula 7.
  • the MG149 targets TIP60 and MOZ.
  • the HAT inhibitor is C646.
  • the IUPAC name of C646 is 4- [4-[[5- (4,5-Dimethyl-2-nitrophenyl) -2-furanyl] methylene] -4,5-dihydro-3-methyl-5-oxo-1H- pyrazol-1-yl] benzoic acid, CAS No. 328968-36-1 and structural formula is Formula 8 below.
  • the C646 targets the P300 / CBP family HAT.
  • the HAT inhibitor is NU9056.
  • the IUPAC name of NU9056 is 5- (1,2-Thiazol-5-yldisulfanyl) -1,2-thiazole, the CAS number is 14450644-28-6, and the structural formula is Formula 9 below.
  • the NU9056 targets TIP60.
  • the HAT inhibitor is CPTH2.
  • the IUPAC name of CPTH2 is 2- [4- (4-chlorophenyl) -2-thiazolyl] hydrazone-cyclopentanone, monohydrochloride, CAS number is 357649-93-5, and structural formula is the following formula 10.
  • the CPTH2 targets GCN5.
  • the HAT inhibitor is 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone.
  • the IUPAC name of 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone is 5-Chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone and CAS number is 748777-47- 1.
  • the structural formula is the following formula 11.
  • the 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone targets P300 and PCAF.
  • the HAT inhibitor is butyrolactone 3 (also known as MB-3).
  • the butyrolactone 3 has an IUPAC name of 3-Methylene-4-hydroxycarbonyl-5- (1-propyl) -tetrahydrofuran-2-one, a CAS number of 7786649-18-6, and a structural formula of the following formula 12.
  • the butyrolactone 3 targets GCN5.
  • the HAT inhibitor is gallic acid.
  • the IUPAC name of the gallic acid is 3,4,5-trihydroxybenzoic acid, the CAS number is 149-91-7, and the structural formula is Formula 13.
  • the gallic acid is a non-specific HAT inhibitor.
  • the HAT inhibitor is ( ⁇ )-epigallocatechin gallate.
  • the IUPAC name of the above ( ⁇ )-epigallocatechin gallate is [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5- trihydroxybenzoate, CAS number is 989-51-5, and structural formula is the following formula 14.
  • the ( ⁇ )-epigallocatechin gallate is a non-specific HAT inhibitor.
  • the HAT inhibitor is EML425.
  • the IUPAC name of the EML425 is 5-[(4-Hydroxy-2,6-dimethylphenyl) methylene] -1,3-bis (phenylmethyl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione, CAS number is 1675821-32-5, the structural formula is the following formula 15.
  • the EML425 targets the P300 / CBP family HAT.
  • the HAT inhibitor is L002.
  • the IUPAC name of L002 is 4- [O-[(4-Methoxyphenyl) sulfonyl] oxime] -2,6-dimethyl-2,5-cyclohexadiene-1,4-dione, CAS number is 321695-57-2, structure
  • the formula is the following formula 16.
  • the above L002 targets P300.
  • the HAT inhibitor is ISOX DUAL.
  • ISOX above The IUPAC name of DUAL is [3- [4- [2- [5- (Dimethyl-1,2-oxazol-4-yl) -1- [2- (morpholin-4-yl) ethyl] -1H-1, 3-benzodiazol-2-yl] ethyl] phenoxy] propyl] dimethylamine, CAS number is not registered, and the structural formula is the following formula 17.
  • the ISOX DUAL targets the bromodomain of CBP and BRD4.
  • the HAT inhibitor is plumbagin.
  • the IUPAC name of plumbagin is 5-Hydroxy-2-methyl-1,4-naphthalened-ione, CAS number is 481-42-5, and the structural formula is Formula 18.
  • the plum bagin targets P300.
  • the HAT inhibitor is TH1834.
  • the IUPAC name of TH1834 is 2- (5- (4-((phenethyl (4- (4- (pyrrolidin-1-ylmethyl) phenoxy) butyl) amino) methyl) phenyl) -2H-tetrazol-2-yl) acetic
  • the acid dihydrochloride and CAS number are not registered, and the structural formula is the following formula 19.
  • the TH1834 targets TIP60.
  • the HAT inhibitor is SPV106.
  • the IUPAC name of the SPV 106 is 2-Pentadecylidene-Propanedioic acid 1,3-diethyl ester, the CAS number is 1036939-38-4, and the structural formula is Formula 20 below.
  • the SPV 106 targets the P300 / CBP family HAT.
  • the SPV 106 is also a PCAF activator.
  • the HAT inhibitor is Windorphen.
  • the IUPAC name of Windorphen is (E) & (Z) -3-Chloro-2,3-bis (4-methoxyphenyl) acrylaldehyde, the CAS number is 19881-70-0, and the structural formula is Formula 21 below. Windorphen is a non-specific HAT inhibitor.
  • the HAT inhibitor is ketomin.
  • the IUPAC name of ketomin is 2,3S, 5aR, 6,10bS, 11-hexahydro-3- (hydroxymethyl) -10b-[(1S, 4S) -3-[[4- (hydroxymethyl) -5,7-dimethyl -6,8-dioxo-2,3-dithia-5,7-diazabicyclo [2.2.2] oct-1-yl] methyl] -1H-indol-1-yl] -2-methyl-3,11aS-epidithio -11aH-pyrazino [1 ′, 2 ′: 1,5] pyrrolo [2,3-b] indole-1,4-dione, CAS number is 1403-36-7, and structural formula is the following formula 22.
  • the ketomin targets the TAZ1 domain of the H1F1 ⁇ / P300 complex.
  • the HAT inhibitor is Remodelin.
  • the IUPAC name of Remodelin is 4- [2- (2-cyclopentylidenehydrazinyl) -1,3-thiazol-4-yl] benzonitrile; hydrobromide, CAS number is 1622921-15-6, and the structural formula is Formula 23 below.
  • the above Remodelin targets NAT10.
  • the HAT inhibitor is envelin.
  • the IUPAC name of the above embellin is 2,5-Dihydroxy-3-undecyl-1,4-benzoquinone, the CAS number is 550-24-3, and the structural formula is Formula 24 below.
  • the envelin targets PCAF.
  • the HAT inhibitor is Ischemin.
  • the IUPAC name of the above Ischemin is 5-[(1E) -2- (2-Amino-4-hydroxy-5-methylphenyl) diazenyl] -2,4-dimethylbenzenesulfonic acid sodium salt, CAS number is 1357059-00-7, structure
  • the formula is the following formula 25.
  • the Ischemin targets the bromodomain of the P300 / CBP family HAT.
  • the HAT inhibitor is CBP30.
  • the IUPAC name of the CBP30 is 8- (3-chloro-4-methoxy-phenethyl) -4- (3,5-dimethyl-isoxazol-4-yl) -9- (2- (morpholin-4-yl) -propyl ) -7,9-diaza-bicyclo [4.3.0] nona-1 (6), 2,4,7-tetraene, CAS number is 1613695-14-9, structural formula is the following formula 26.
  • the CBP30 targets the bromodomain of the P300 / CBP family HAT.
  • the HAT inhibitor is KG501 (also known as naphthol AS-E phosphate).
  • KG501 also known as naphthol AS-E phosphate.
  • the IUPAC name of the above KG501 is 3-[(4-chlorophenyl) carbamoyl] -2-naphthyl dihydrogen phosphate; N- (4-Chlorophenyl) -3- (phosphonooxy) naphthalene-2-carboxamide, CAS number is 18228-17-6
  • the structural formula is the following formula 27.
  • the KG501 targets the KIX domain of the P300 / CBP family HAT.
  • 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, garcinol, anacardic acid, MG149, gallic acid, ( ⁇ )-epigallocatechin gallate, plumbagin And embellin is a compound derived from polyphenol.
  • CTK7A anacardic acid
  • MG149 gallic acid
  • C646 gallic acid
  • ( ⁇ )-epigallocatechin gallate and plumbagin are benzoic acid derivatives.
  • CTK7A, C646, CPTH2, ISOX DUAL, TH1834, and Remodelin contain a heterocycle in the structure.
  • 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, butyrolactone 3, SPV106, and Windorphen are ⁇ - ⁇ unsaturated carbonyl compounds.
  • the HAT inhibitor may be a derivative or salt of the substances described above.
  • a derivative or salt of the above-mentioned substance as a HAT inhibitor, (1) the preventive or therapeutic effect of cataract is increased, (2) the safety of the substance to the human body is increased, and (3) the preparation is easy to handle. Effects such as obtaining physical properties can be imparted.
  • “derivative” means a group of compounds produced by substituting a part of the compound in the molecule with another functional group or another atom for a specific compound.
  • Examples of the other functional groups include alkyl groups, alkoxy groups, alkylthio groups, aryl groups, aryloxy groups, arylthio groups, arylalkyl groups, arylalkoxy groups, arylalkylthio groups, arylalkenyl groups, arylalkynyl groups, allyls.
  • Examples of the other atoms include a carbon atom, a hydrogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, and a halogen atom.
  • salt is not limited as long as it is a salt that is physiologically acceptable to be administered to a subject as a pharmaceutical product.
  • salts include alkali metal salts (potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamines).
  • N N, N'-dibenzylethylenediamine salt
  • organic acid salt acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate
  • inorganic acid salts hydroochloride, hydrobromide, sulfate, phosphate, etc.
  • HAT inhibitors Derivatives or salts of the substances described above as examples of HAT inhibitors can be produced by known methods.
  • the prophylactic or therapeutic agent for cataract is administered to a subject.
  • the subject is a human.
  • the subject is a non-human animal. Examples of the non-human animals include mammals other than humans (cow, pig, sheep, goat, horse, dog, cat, rabbit, mouse, rat, etc.).
  • the prophylactic or therapeutic agent for cataract can be administered to a subject by any route of administration.
  • the administration route include oral administration, parenteral administration, transdermal administration, transmucosal administration, and intravenous administration.
  • the dosage form of the prophylactic or therapeutic agent for cataract may be an internal medicine, an external medicine, an injection, a suppository, an inhalant, an eye drop and the like.
  • parenteral administration is preferred, ophthalmic administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, and subtenon administration are more preferred, and ophthalmic administration is even more preferred.
  • eye drops or injections are preferable, and eye drops are more preferable.
  • the reasons why ophthalmic solutions are preferable are that the route until the active ingredient is delivered to the lens is short, that other organs are difficult to irritate, that there is little invasion, and that the effect on the whole body is small (the punctum after instillation) The effects on the whole body can be further suppressed by compression), administration is simple, repeated administration is possible, and patients can be self-administered. For this reason, it can be expected that the effect of preventing or treating cataract is made quicker or increased.
  • the preventive or therapeutic agent for cataract contains a HAT inhibitor as an active ingredient.
  • active ingredient intends a substance that can provide a prophylactic or therapeutic effect against one or more symptoms.
  • the preventive or therapeutic agent for cataract may contain only one type of HAT inhibitor, or may contain a combination of two or more types of HAT inhibitors. By combining two or more HAT inhibitors, a synergistic effect that cannot be predicted from the effects of the individual HAT inhibitors can be obtained.
  • HAT inhibitors examples include (1) a combination of CBP30 and CPTH2, and (2) a combination of C646 and CPTH2.
  • the concentration of the HAT inhibitor contained in the preventive or therapeutic agent for cataract varies depending on the type of the HAT inhibitor, the administration route and the dosage form selected.
  • the lower limit of the concentration of the HAT inhibitor is 0.001 ⁇ M or more, 0.002 ⁇ M or more, 0.005 ⁇ M or more, 0.01 ⁇ M or more, 0.02 ⁇ M or more, 0.05 ⁇ M or more, 0.1 ⁇ M or more, 0.
  • the upper limit of the concentration of the HAT inhibitor is 0.01 ⁇ M or less, 0.02 ⁇ M or less, 0.05 ⁇ M or less, 0.1 ⁇ M or less, 0.2 ⁇ M or less, 0.5 ⁇ M or less, 1 ⁇ M or less, 2 ⁇ M or less, 3 ⁇ M 4 ⁇ M or less, 5 ⁇ M or less, 6 ⁇ M or less, 7 ⁇ M or less, 8 ⁇ M or less, 9 ⁇ M or less, 10 ⁇ M or less, 20 ⁇ M or less, 30 ⁇ M or less, 40 ⁇ M or less, 50 ⁇ M or less, 60 ⁇ M or less, 70 ⁇ M or less, 80 ⁇ M or less, 90 ⁇ M or less, 100 ⁇ M or less, 200 ⁇ M or less, 300 ⁇ M or less, 400 ⁇ M or less, 500 ⁇ M or less, 1000 ⁇ M or less, 2000 ⁇ M or less, or 5000 ⁇ M or less.
  • the concentration of the HAT inhibitor is 0.001 to 0.01 ⁇ M, 0.002 to 0.02 ⁇ M, 0.005 to 0.05 ⁇ M, 0.01 to 0.1 ⁇ M, 0.02 to 0.2 ⁇ M.
  • the preventive or therapeutic agent for cataract according to one embodiment of the present invention may contain components other than the HAT inhibitor.
  • Ingredients other than the HAT inhibitor may be active ingredients or not active ingredients.
  • the active ingredient may be an active ingredient for symptoms related to cataract (symptoms of cataracts, complications of cataracts, etc.), or an active ingredient for symptoms not related to cataracts It may be.
  • the types of components that are not active components include buffers, pH adjusters, tonicity agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, and dilutions. Agents, solvents, solubilizers, stabilizers, fillers, binders, surfactants, stabilizers and the like.
  • Examples of the buffer include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonic acid or carbonate, tartaric acid or tartrate, ⁇ -aminocaproic acid, trometamol Etc.
  • Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.
  • Examples of the borate include borax, sodium borate, and potassium borate.
  • Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate.
  • Examples of the acetate include sodium acetate and potassium acetate.
  • Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate.
  • Examples of the tartrate salt include sodium tartrate and potassium tartrate.
  • pH adjusting agents examples include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide and the like.
  • tonicity agent examples include ionic tonicity agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and nonionic tonicity agents (glycerin, propylene glycol, sorbitol, mannitol, etc.). Can be mentioned.
  • preservatives examples include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.
  • antioxidants examples include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
  • high molecular weight polymer examples include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, atelocollagen and the like.
  • telocollagen as a high molecular weight polymer because the absorption rate of the HAT inhibitor is increased.
  • the prophylactic or therapeutic agent for cataract according to one embodiment of the present invention may contain an active ingredient and / or a pharmaceutical additive known to those skilled in the art, other than those exemplified above.
  • the prophylactic or therapeutic agent for cataract according to one embodiment of the present invention can be formulated by a known technique using ingredients other than the HAT inhibitor and the HAT inhibitors exemplified above as raw materials.
  • the dose is not limited as long as a desired effect is obtained.
  • the administration interval is not limited as long as a desired effect is obtained.
  • the administration interval is usually once every 1 hour to 6 months, preferably once per hour, once every 2 hours, once every 3 hours, once every 6 hours, once every 12 hours, Once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, three weeks 1 time, 1 time in 1 month, 1 time in 2 months, 1 time in 3 months, 1 time in 4 months, 1 time in 5 months, 1 time in 6 months, more preferably At least once a day, at least once every two days, at least once every three days, at least once every four days, at least once every five days, at least once every six days, at least once a week is there.
  • the cataract preventive or therapeutic agent according to one embodiment of the present invention may be prescribed in combination with a drug for preventing or treating cataract and / or other diseases.
  • FIG. 1 (a) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to one embodiment of the present invention.
  • This mechanism of action is a model in which the expression of PLK3 located upstream of the apoptosis-related gene P53 is suppressed by a HAT inhibitor.
  • FIG. 1 (b) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to another embodiment of the present invention.
  • This mechanism of action is a model in which ALDH1A1 expression is promoted by HAT inhibitors.
  • FIG. 1 (c) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to still another embodiment of the present invention.
  • This mechanism of action is a model in which GJA1 expression is promoted by HAT inhibitors.
  • HAT inhibitor When no HAT inhibitor is administered, the function of activating GJA1 in HAT is suppressed, and the cell-cell adhesion of lens epithelial cells is reduced. As a result, moisture is taken into the crystalline lens and turbidity occurs as the osmotic pressure increases.
  • the expression of GJA1 is promoted by promoting the function of HAT (for example, the substance described in [2-1]) by the HAT inhibitor, As a result, cataract is prevented or treated.
  • HDAC histone deacetylase
  • An example of a HAT inhibitor having such a mechanism of action is anacardic acid.
  • HAT inhibitors prevent or treat cataracts by intervening in epigenetic control mechanisms of gene expression. Therefore, all the preventive or therapeutic agents for cataracts containing a substance having a function as a HAT inhibitor as an active ingredient are included in the scope of the present invention.
  • One embodiment of the present invention is a method for preventing or treating cataract using a prophylactic or therapeutic agent for cataract containing an HAT inhibitor as an active ingredient.
  • Example 1 Using a diabetic cataract model using a galactose-added medium, the following cataract preventive effects of HAT inhibitors were investigated.
  • Example 1-1 The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.).
  • the lens extracted from the right eye was cultured in a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA), and used as a model for developing diabetic cataract.
  • the lens extracted from the left eye was obtained by adding 30 mM galactose and 40 ⁇ M 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane (abcam) to the M199 medium. Incubated in An incubator was used for the culture, and the temperature was maintained at 37 ° C.
  • 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is a HAT inhibitor that targets HAT of the P300 / CBP family.
  • the lens cultured in the medium supplemented with 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is The turbidity of the cortex was kept low compared to the lens cultured in a medium not added with -bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane.
  • Example 1-2 The lens was extracted from the left eye, and the experiment was carried out in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 ⁇ M CTK7A (EMD Millipore). It was. CTK7A is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
  • the lens cultured in the medium supplemented with CTK7A suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CTK7A. It was done.
  • Example 1-3 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 2 ⁇ M garcinol (manufactured by Selleckchem) were added to the M199 medium. .
  • Garcinol is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
  • the lens cultured in the medium added with garcinol suppresses the turbidity of the cortex to be lower than the lens cultured in the medium not added with garcinol. It was done.
  • Example 1-4 The lens was extracted from the left eye, and the experiment was carried out in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 20 ⁇ M anacardic acid (abcam). It was. Anacardic acid is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
  • the lens cultured in the medium to which the anacardic acid was added was more turbid in the cortex than the lens cultured in the medium to which the anacardic acid was not added. It was kept low.
  • Example 1-5 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 50 ⁇ M MG149 (manufactured by Selleckchem) were added to the M199 medium. . MG149 is a HAT inhibitor that targets TIP60 and MOZ. The results are shown in FIG.
  • the lens cultured in the medium supplemented with MG149 has a slightly lower turbidity in the cortex than the lens cultured in the medium not added with MG149. It was suppressed.
  • Example 1-6 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 40 ⁇ M C646 (manufactured by SIGMA) were added to the M199 medium. .
  • C646 is a HAT inhibitor that targets P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium supplemented with C646 has a lower turbidity in the cortex than the lens cultured in the medium not supplemented with C646. It was done.
  • Example 1-7 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M CPTH2 (manufactured by Cayman) to the M199 medium. .
  • CPTH2 is a HAT inhibitor that targets GCN5. The results are shown in FIG.
  • the lens cultured in the medium added with CPTH2 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CPTH2. It was done.
  • Example 1-8 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 500 ⁇ M butyrolactone 3 (abcam) to the M199 medium. It was. Butyrolactone 3 is a HAT inhibitor that targets GCN5. The results are shown in FIG.
  • the lens cultured in the medium added with butyrolactone 3 has more turbidity in the cortex than the lens cultured in the medium not added with butyrolactone 3. It was kept low.
  • Example 1-9 The lens extracted from the left eye was subjected to the same procedure as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 ⁇ M gallic acid (manufactured by SIGMA). It was. In addition, gallic acid is a non-specific HAT inhibitor. The results are shown in FIG.
  • the lens cultured in the medium added with gallic acid is more turbid in the cortex than the lens cultured in the medium not added with gallic acid. It was a little lower.
  • Example 1-10 Example 1 except that the lens removed from the left eye was cultured in the above M199 medium supplemented with 30 mM galactose and 50 ⁇ M ( ⁇ )-epigallocatechin gallate (Wako Pure Chemical Industries, Ltd.). Experiments were performed in the same procedure as for -1. Note that ( ⁇ )-epigallocatechin gallate is a non-specific HAT inhibitor. The results are shown in FIG.
  • the lens cultured in the medium supplemented with the ( ⁇ )-epigallocatechin gallate was added to the medium without the addition of the ( ⁇ )-epigallocatechin gallate.
  • the turbidity of the cortex was somewhat lower.
  • Example 1-11 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 20 ⁇ M ISOX DUAL (manufactured by SIGMA) were added to the M199 medium. It was. ISOX DUAL is a HAT inhibitor that targets the bromodomain of CBP and BRD4. The results are shown in FIG.
  • the lens cultured in the medium supplemented with the above ISOX DUAL is more turbid in the cortex than the lens cultured in the medium not added with the above ISOX DUAL. It was kept low.
  • Example 1-12 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 2 ⁇ M plumbagin (manufactured by SIGMA) were added to the M199 medium. .
  • Plumbagin is a HAT inhibitor that targets P300. The results are shown in FIG.
  • the lens cultured in the medium to which the plumbagin was added had less turbidity in the cortex compared to the lens cultured in the medium to which the plumbagin was not added. It was done.
  • Example 1-13 The lens was extracted from the left eye, and the experiment was performed in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 ⁇ M TH1834 (manufactured by axon medchem). It was. TH1834 is a HAT inhibitor that targets TIP60. The results are shown in FIG.
  • the lens cultured in the medium added with TH1834 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with TH1834. It was done.
  • Example 1-14 The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 100 ⁇ M SPV106 (manufactured by SIGMA) were added to the M199 medium. . SPV106 is a HAT inhibitor that targets the P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium to which the SPV 106 is added suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium to which the SPV 106 is not added. It was done.
  • Example 1-15 An experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M Windorphen (manufactured by SIGMA) to the M199 medium. . Windorphen is a non-specific HAT inhibitor. The results are shown in FIG.
  • the lens cultured in the medium added with Windorphen suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with Windorphen. It was done.
  • Example 1-16 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M Remodelin (manufactured by Cayman) to the M199 medium. . Remodelin is a HAT inhibitor that targets NAT10. The results are shown in FIG.
  • the lens cultured in the medium added with Windorphen suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with Windorphen. It was done.
  • Example 1-17 The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 ⁇ M Embelin (abcam) to the M199 medium.
  • Embelin is a HAT inhibitor that targets PCAF. The results are shown in FIG.
  • the lens cultured in the medium supplemented with the above-described embellin suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with the above-described embellin. It was done.
  • Example 1-18 The lens extracted from the left eye was subjected to the same procedure as in Example 1-1 except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 200 ⁇ M EML425 (manufactured by axon medchem). It was. EML425 is a HAT inhibitor that targets P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium to which the EML425 is added suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium to which the EML425 is not added. It was done.
  • Example 1-19 An experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 5 ⁇ M CBP30 (manufactured by Cayman) to the M199 medium.
  • CBP30 is a HAT inhibitor that targets the bromodomain of the P300 / CBP family HAT. The results are shown in FIG.
  • the lens cultured in the medium added with CBP30 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CBP30. It was done.
  • Example 1-1 The same procedure as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 0.8 ⁇ M TSA (manufactured by Wako Pure Chemical Industries, Ltd.) were added to the M199 medium. The experiment was conducted. TSA is a histone deacetylase (HDAC) inhibitor. The results are shown in FIG.
  • HDAC histone deacetylase
  • the lens cultured in the medium to which TSA was added increased the turbidity of the cortex compared with the lens cultured in the medium to which TSA was not added. It was.
  • Example 2 The concentration of the HAT inhibitor (C646) or HDAC inhibitor (TSA) added to the medium was changed, and the turbidity generated in the lens was quantified.
  • the lens extracted from the left eye was cultured in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 40 ⁇ M C646 (manufactured by SIGMA).
  • a photomicrograph of the later lens was obtained.
  • the above-mentioned micrograph was converted into a gray scale image using Adobe photoshop (registered trademark) cs6.
  • Example 3 The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from both the left and right eyes was cultured in a medium in which 30 mM galactose was added to M199 medium (manufactured by SIGMA) for 2 days, and used as a model for developing diabetic cataract. Thereafter, the lens of the left eye was transferred to a medium supplemented with 30 mM galactose and 40 ⁇ M C646. On the other hand, the lens of the right eye did not change the medium.
  • the lens transferred to the medium added with C646 and cultured has a lower turbidity of the cortex than the lens that has been cultured in the medium not added with C646. It was.
  • Example 4 Microarrays were used to investigate gene expression and to estimate the mechanism by which HAT inhibitors prevent or treat cataracts.
  • M199 medium (manufactured by SIGMA), medium obtained by adding 30 mM galactose to M199 medium, medium obtained by adding 30 mM galactose and 40 ⁇ M HAT inhibitor (C646) to M199 medium, and 30 mM galactose to M99 medium And a medium supplemented with 0.8 ⁇ M HDAC inhibitor (TSA).
  • TSA 0.8 ⁇ M HDAC inhibitor
  • RNA extraction methods are described in the TRIZOL (registered trademark) instruction manual.
  • the sample prepared by the above procedure was used as a sample for microarray analysis.
  • microarray chip manufactured by Affymetrix
  • gene expression in each lens was examined.
  • the obtained data was analyzed using Excel (registered trademark). From the analysis results, genes that showed different expression levels were selected between the lens cultured in the HAT inhibitor-added medium and the lens cultured in the HDAC inhibitor-added medium.
  • the expression level of a gene in a lens cultured in a medium containing only galactose was set to 1, and a gene corresponding to the following condition (i) or (ii) was selected.
  • the expression level in the M199 medium (control) and the medium added with galactose and HAT inhibitor is 1.5 or more, and the expression level in the medium added with galactose and HDAC inhibitor is 0.5 or less.
  • the expression level in the M199 medium (control) and the medium to which galactose and HAT inhibitors are added is 0.5 or less, and the expression level in the medium to which galactose and HDAC inhibitors are added is 1.5 or more.
  • Table 2 shows the genes corresponding to the above conditions and the expression levels of the genes.
  • FIG. 1 (a) shows an example of the mechanism of action for preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of PLK3 among the genes listed in Table 2.
  • FIG. 1B shows an example of the action mechanism of the effect of preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of ALDH1A1.
  • FIG. 1 (c) shows an example of the action mechanism of the effect of preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of GJA1 (Cx43).
  • Example 5 The therapeutic effect of cataract by the combination of HAT inhibitors was examined.
  • Example 5-1 A medium in which 30 mM galactose and DMSO having a final concentration of 0.8% were added to M199 medium (manufactured by SIGMA) was prepared.
  • M199 medium manufactured by SIGMA
  • a lens extracted from both left and right eyes of a 6-week-old SD rat was cultured at 37 ° C. under 5% CO 2 for 4 days to develop diabetic cataract.
  • the lens of the left eye was transferred to a medium supplemented with (1) 30 mM galactose, and (2) 10 ⁇ M CBP30 and 80 ⁇ M CPTH2 (both dissolved in DMSO having a final concentration of 0.8%).
  • a medium in which 30 mM galactose and DMSO with a final concentration of 0.8% were added to M199 medium was prepared again and transferred to the medium.
  • the lens was immersed in an FG (Formalin-Glutaraldehyde) solution (Formalin: manufactured by Muto Chemical Co., Ltd., Glutaraldehyde: manufactured by Wako Pure Chemical Industries, Ltd.) at 4 ° C. for 3 days, and then immersed in a 10% formalin solution.
  • FG Formin-Glutaraldehyde
  • the new histochemical laboratory was commissioned to prepare stained sections.
  • FIG. 1 A micrograph was taken in which the section was magnified 100 times with IX70 (Olympas). The result is shown in FIG. In the figure, the left side is the whole image of the above section, and the right side is an enlarged image near the equator.
  • Experiment 1-1 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 10 ⁇ M CBP30 (dissolved in DMSO at a final concentration of 0.8%).
  • Experiment 1-2 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 80 ⁇ M CPTH2 (dissolved in DMSO at a final concentration of 0.8%).
  • the lens transferred and cultured in the medium to which the combination of CBP30 and CPTH2 was added had only one of CBP30 or CPTH2 added.
  • the turbidity of the cortex was suppressed to be lower than that of the lens that had been transferred to the cultured medium and cultured.
  • Example 5-1 the medium for transferring the lens of the left eye was (1) 30 mM galactose, and (2) 40 ⁇ M C646 and 80 ⁇ M CPTH2 (both dissolved in DMSO at a final concentration of 0.8%) The lens was cultured by the same procedure except that the medium was changed to a medium supplemented with. The result is shown in FIG.
  • Experiment 2-1 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 40 ⁇ M C646 (dissolved in DMSO at a final concentration of 0.8%).
  • Experiment 2-2 The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 80 ⁇ M CPTH2 (dissolved in DMSO at a final concentration of 0.8%).
  • the lens transferred to the medium supplemented with the combination of C646 and CPTH2 was cultured in the cortex compared with the lens that had been cultured in the medium without the combination of C646 and CPTH2.
  • the turbidity of was kept low.
  • the lens transferred to the medium added with the combination of C646 and CPTH2 was transferred to the medium added with only one of C646 or CPTH2.
  • the turbidity of the cortex was lower than that of the cultured lens.
  • Example 6 Under in vivo conditions, the effect of HAT inhibitors to prevent cataracts was examined.
  • the lens was extracted from both the left and right eyes, and a micrograph magnified to 10 with SZX12 (Olympas) was taken. The result is shown in FIG.
  • the injection into the anterior chamber was performed only once.
  • food containing 25% galactose was continuously fed.
  • the present invention can be used as an agent for preventing or treating cataract.

Abstract

Provided are: a novel preventive agent and a novel therapeutic agent for cataracts; and use of an HAT inhibitor for production thereof. The preventive agent or therapeutic agent for cataracts according to the present invention contains an HAT inhibitor as an active ingredient.

Description

白内障の予防剤、治療剤、およびこれらを製造するためのＨＡＴ阻害剤の使用Cataract preventive and therapeutic agents, and use of HAT inhibitors to produce them
　本発明は、白内障の予防剤、治療剤、およびこれらを製造するためのＨＡＴ阻害剤の使用に関する。より具体的には、ＨＡＴ阻害剤を有効成分として含有している白内障の予防剤または治療剤に関する。 The present invention relates to a preventive agent, a therapeutic agent for cataract, and use of a HAT inhibitor for producing them. More specifically, the present invention relates to a preventive or therapeutic agent for cataract containing a HAT inhibitor as an active ingredient.
　白内障は、水晶体が混濁することによって、視力の低下が引き起こされる疾患である。白内障の種類によって異なるが、白内障に罹患した水晶体は、核、皮質または後嚢に白濁を生じる。白内障の種類には、加齢白内障、糖尿病白内障などが存在する。このうち罹患者数が最も多い加齢白内障は、加齢と共に有所見率が増加し、初期の混濁も含めると、日本国における６０歳代の有所見率は６６～８５％、７０歳代の有所見率は８４～９７％、８０歳以上では１００％に達する。これに対し、糖尿病白内障は６０歳以下の罹患者が多く、若年層でも発症しうる疾患である。 Cataract is a disease in which a reduction in visual acuity is caused by turbidity of the lens. Depending on the type of cataract, a lens affected by cataract develops cloudiness in the nucleus, cortex or posterior capsule. Types of cataracts include age-related cataracts and diabetic cataracts. Of these, age-related cataract, which has the highest number of affected individuals, has an increased prevalence rate with age, and including the initial opacity, the prevalence rate in the 60s in Japan is 66-85%, in the 70s The prevalence rate is 84-97%, reaching 100% for people over 80 years old. On the other hand, diabetic cataract is a disease that has many affected people under 60 years old and can develop even in young people.
　白内障への処置は、混濁の発生後における外科手術による治療が主であるが、予防剤または治療剤の投与も行われている。上記予防剤または進行抑制剤の一例として、非特許文献１はグルタチオン、非特許文献２はピレノキシンを報告している。 The main treatment for cataracts is surgical treatment after the occurrence of turbidity, but prophylactic or therapeutic agents are also administered. As an example of the preventive agent or the progression inhibitor, Non-Patent Document 1 reports glutathione, and Non-Patent Document 2 reports pirenoxine.
　しかしながら、上述のような従来技術は、白内障の予防または治療効果において、改善の余地を残していた。 However, the conventional techniques as described above leave room for improvement in the effect of preventing or treating cataracts.
　本発明は、上記従来の問題点に鑑みなされたものであって、新規な白内障の予防剤、治療剤、およびこれらを製造するためのＨＡＴ阻害剤の使用を提供することを目的とする。 The present invention has been made in view of the above-mentioned conventional problems, and an object thereof is to provide a novel cataract preventive agent, therapeutic agent, and use of a HAT inhibitor for producing them.
　本発明者らは、上記目的を達成するために鋭意検討を重ねた結果、ＨＡＴ阻害剤が白内障を予防および治療しうることを見出し、本発明を完成するに至った。すなわち、本発明は以下の構成からなるものである。 As a result of intensive studies to achieve the above object, the present inventors have found that a HAT inhibitor can prevent and treat cataract, and have completed the present invention. That is, the present invention has the following configuration.
　＜１＞ＨＡＴ阻害剤を有効成分として含有している、白内障の予防剤または治療剤。 <1> A preventive or therapeutic agent for cataract, which contains a HAT inhibitor as an active ingredient.
　＜２＞上記ＨＡＴ阻害剤は、ＨＡＴ１、ＮＡＡ６０、ＧＣＮ５、ＰＣＡＦ、ＴＩＰ６０、ＭＯＺ、ＭＯＲＦ、ＨＢＯ１、ＭＯＦ、Ｐ３００、ＣＢＰ、ＴＡＦ１、ＴＩＦＩＩＩＣ９０、ＳＲＣ１、ＳＣＲ３、Ｐ６００、ＣＬＯＣＫおよびＮＡＴ１０からなる群より選択される１種以上の物質を標的とするものである、＜１＞に記載の白内障の予防剤または治療剤。 <2> The HAT inhibitor is selected from the group consisting of HAT1, NAA60, GCN5, PCAF, TIP60, MOZ, MORF, HBO1, MOF, P300, CBP, TAF1, TIFIIIC90, SRC1, SCR3, P600, CLOCK and NAT10. The prophylactic or therapeutic agent for cataract according to <1>, which targets at least one kind of substance.
　＜３＞上記ＨＡＴ阻害剤は、ポリフェノール由来の化合物、構造中にヘテロ環を含んでいる化合物、安息香酸誘導体、またはα－β不飽和カルボニル化合物である、＜１＞または＜２＞に記載の白内障の予防剤または治療剤。 <3> The HAT inhibitor is a compound derived from polyphenol, a compound containing a heterocycle in the structure, a benzoic acid derivative, or an α-β unsaturated carbonyl compound, according to <1> or <2> A preventive or therapeutic agent for cataracts.
　＜４＞上記ＨＡＴ阻害剤は、クルクミン、２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサン、ＣＴＫ７Ａ、Ｅｐｉｇｅｎｅｔｉｃ　Ｍｕｌｔｉｐｌｅ　Ｌｉｇａｎｄ、ガルシノール、アナカルド酸、ＭＧ１４９、Ｃ６４６、ＮＵ９０５６、ＣＰＴＨ２、５－クロロ－２－（４－ニトロフェニル）－３（２Ｈ）－イソチアゾロン、ブチロラクトン３、没食子酸、（－）－エピガロカテキンガラート、ＥＭＬ４２５、Ｌ００２、ＩＳＯＸ　ＤＵＡＬ、プルンバギン、ＴＨ１８３４、ＳＰＶ１０６、Ｗｉｎｄｏｒｐｈｅｎ、ケトミン、Ｒｅｍｏｄｅｌｉｎ、エンベリン、Ｉｓｃｈｅｍｉｎ、ＣＢＰ３０およびＫＧ５０１からなる群より選択される１種以上の化合物、または当該化合物の誘導体もしくは塩である、＜１＞または＜２＞に記載の白内障の予防剤または治療剤。 <4> The above HAT inhibitors include curcumin, 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, Epigenetic Multiple Ligand, garcinol, anacardic acid, MG149, C646, NU9056, CPTH2 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone, butyrolactone 3, gallic acid, (−)-epigallocatechin gallate, EML425, L002, ISOX DUAL, plumbagin, TH1834, SPV106, One or more compounds selected from the group consisting of Windorphen, ketomin, Remodelin, Embelin, Ischemin, CBP30 and KG501, or a derivative or salt of the compound Prophylactic or therapeutic agents of cataracts according to <1> or <2>.
　＜５＞投与剤型が点眼剤である、＜１＞～＜４＞の何れか１つに記載の白内障の予防剤または治療剤。 <5> The preventive or therapeutic agent for cataract according to any one of <1> to <4>, wherein the dosage form is an eye drop.
　＜６＞上記白内障は、糖尿病白内障である、＜１＞～＜５＞の何れか１つに記載の白内障の予防剤または治療剤。 <6> The preventive or therapeutic agent for cataract according to any one of <1> to <5>, wherein the cataract is diabetic cataract.
　＜７＞白内障の予防剤または治療剤を製造するための、ＨＡＴ阻害剤の使用。 <7> Use of a HAT inhibitor to produce a preventive or therapeutic agent for cataract.
　本発明の一態様によれば、新規な白内障の予防剤または治療剤が提供される。 According to one embodiment of the present invention, a novel preventive or therapeutic agent for cataract is provided.
（ａ）本発明の一実施形態に係る白内障の予防剤または治療剤の、作用機序の例を表すモデル図である。（ｂ）本発明の一実施形態に係る白内障の予防剤または治療剤の、他の作用機序の例を表すモデル図である。（ｃ）本発明の一実施形態に係る白内障の予防剤または治療剤の、更に他の作用機序の例を表すモデル図である。(A) It is a model figure showing the example of an action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention. (B) It is a model figure showing the example of the other action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention. (C) It is a model figure showing the example of the further another action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention. （ａ）２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサンによる白内障の予防効果を示す写真である。（ｂ）ＣＴＫ７Ａによる白内障の予防効果を示す写真である。（ｃ）ガルシノールによる白内障の予防効果を示す写真である。（ｄ）アナカルド酸による白内障の予防効果を示す写真である。（ｅ）ＭＧ１４９による白内障の予防効果を示す写真である。(A) A photograph showing the preventive effect of 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane on cataract. (B) It is a photograph which shows the prevention effect of the cataract by CTK7A. (C) It is a photograph which shows the prevention effect of the cataract by garcinol. (D) It is a photograph which shows the prevention effect of the cataract by an anacardic acid. (E) It is a photograph which shows the prevention effect of the cataract by MG149. （ａ）Ｃ６４６による白内障の予防効果を示す写真である。（ｂ）ＣＰＴＨ２による白内障の予防効果を示す写真である。（ｃ）ブチロラクトン３による白内障の予防効果を示す写真である。（ｄ）没食子酸による白内障の予防効果を示す写真である。（ｅ）（－）－エピガロカテキンガラートによる白内障の予防効果を示す写真である。(A) It is a photograph which shows the prevention effect of the cataract by C646. (B) It is a photograph which shows the prevention effect of the cataract by CPTH2. (C) A photograph showing the effect of butyrolactone 3 on preventing cataracts. (D) It is a photograph which shows the prevention effect of the cataract by a gallic acid. (E) A photograph showing the prevention effect of cataract by (−)-epigallocatechin gallate. （ａ）ＩＳＯＸ　ＤＵＡＬによる白内障の予防効果を示す写真である。（ｂ）プルンバギンによる白内障の予防効果を示す写真である。（ｃ）ＴＨ１８３４による白内障の予防効果を示す写真である。（ｄ）ＳＰＶ１０６による白内障の予防効果を示す写真である。（ｅ）Ｗｉｎｄｏｒｐｈｅｎによる白内障の予防効果を示す写真である。(A) It is a photograph which shows the prevention effect of the cataract by ISOX DUAL. (B) It is a photograph which shows the prevention effect of the cataract by a plum baggin. (C) It is a photograph which shows the prevention effect of the cataract by TH1834. (D) It is a photograph which shows the prevention effect of the cataract by SPV106. (E) It is a photograph which shows the prevention effect of the cataract by Windorphen. （ａ）Ｒｅｍｏｄｅｌｉｎによる白内障の予防効果を示す写真である。（ｂ）エンベリンによる白内障の予防効果を示す写真である。（ｃ）ＥＭＬ４２５による白内障の予防効果を示す写真である。（ｄ）ＣＢＰ３０による白内障の予防効果を示す写真である。（ｅ）ＴＳＡによる白内障の促進効果を示す写真である。(A) It is a photograph which shows the prevention effect of the cataract by Remodelin. (B) It is a photograph which shows the prevention effect of the cataract by an embelline. (C) It is a photograph which shows the prevention effect of the cataract by EML425. (D) It is a photograph which shows the prevention effect of the cataract by CBP30. (E) It is a photograph which shows the promotion effect of the cataract by TSA. ＨＤＡＣ阻害剤による水晶体白濁の促進、およびＨＡＴ阻害剤による水晶体白濁の抑制を定量化したグラフである。It is the graph which quantified promotion of lens white turbidity by a HDAC inhibitor, and suppression of lens white turbidity by a HAT inhibitor. ＨＡＴ阻害剤（Ｃ６４６）による白内障治療効果を示す写真である。It is a photograph which shows the cataract treatment effect by a HAT inhibitor (C646). （ａ）ＣＢＰ３０とＣＰＴＨ２との組み合わせによる、白内障治療効果を示す写真である。（ｂ）ＣＢＰ３０とＣＰＴＨ２との組み合わせを投与してから４日後における、水晶体の切片を示す写真である。(A) It is a photograph which shows the cataract treatment effect by the combination of CBP30 and CPTH2. (B) A photograph showing a slice of the lens 4 days after administration of the combination of CBP30 and CPTH2. （ａ）ＣＢＰ３０による白内障治療効果を示す写真である。（ｂ）ＣＰＴＨ２による白内障治療効果を示す写真である。(A) It is a photograph which shows the cataract treatment effect by CBP30. (B) It is a photograph which shows the cataract treatment effect by CPTH2. Ｃ６４６とＣＰＴＨ２との組み合わせによる、白内障治療効果を示す写真である。It is a photograph which shows the cataract treatment effect by the combination of C646 and CPTH2. （ａ）Ｃ６４６による白内障治療効果を示す写真である。（ｂ）ＣＰＴＨ２による白内障治療効果を示す写真である。(A) It is a photograph which shows the cataract treatment effect by C646. (B) It is a photograph which shows the cataract treatment effect by CPTH2. （ａ）in vivoにおける、ＨＡＴ阻害剤（Ｃ６４６）の白内障予防効果を検討する実験の概要を示す模式図である。（ｂ）図１２の（ａ）の実験結果を示す写真である。(A) It is a schematic diagram which shows the outline | summary of the experiment which investigates the cataract prevention effect of the HAT inhibitor (C646) in in vivo. (B) It is a photograph which shows the experimental result of (a) of FIG.
　本発明の一実施形態について説明すると以下の通りであるが、本発明はこれに限定されるものではない。本発明は、以下に説明する各構成に限定されるものではなく、特許請求の範囲に示した範囲で種々の変更が可能であり、異なる実施形態及び実施例にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態及び実施例についても本発明の技術的範囲に含まれる。また、本明細書中に記載された文献の全てが、本明細書中において参考文献として援用される。 An embodiment of the present invention will be described as follows, but the present invention is not limited to this. The present invention is not limited to each configuration described below, and various modifications can be made within the scope shown in the claims, and technical means disclosed in different embodiments and examples respectively. Embodiments and examples obtained by appropriately combining them are also included in the technical scope of the present invention. Moreover, all the literatures described in this specification are used as a reference in this specification.
　本明細書中、数値範囲に関して「Ａ～Ｂ」と記載した場合、当該記載は「Ａ以上Ｂ以下」を意図する。 In this specification, when “A to B” is described with respect to a numerical range, the description is intended to be “A or more and B or less”.
　〔１．用語の定義〕
　［１－１．白内障］
　本明細書において「白内障」とは、水晶体に混濁を生じる疾患一般を意図する。白内障によって水晶体に生じる混濁には、例えば、皮質混濁、核混濁、後嚢下混濁、皮質スポーク状混濁、前嚢下混濁、線維ひだ、水隙、核周囲の徹照下点状混濁、水疱、点状混濁、冠上混濁などの類型がある。また、本明細書において「白内障」とは、加齢白内障の他に、糖尿病白内障、先天白内障、外傷性白内障、アトピー白内障、放射線白内障、ステロイド白内障といった併発白内障などの病型を総称した疾患を意図する。 [1. Definition of terms〕
[1-1. Cataract]
As used herein, the term “cataract” refers to any disease that causes opacity in the lens. The opacity that occurs in the lens due to cataract includes, for example, cortical turbidity, nuclear turbidity, posterior subcapsular turbidity, cortical spoke turbidity, anterior capsular turbidity, fibrous folds, water space, transilluminated spot-like turbidity around the nucleus, blisters, There are types such as punctate turbidity and turbidity on the crown. In addition, the term “cataract” in this specification is intended to refer to diseases that collectively refer to disease types such as diabetic cataract, congenital cataract, traumatic cataract, atopic cataract, radiation cataract, and steroid cataract. To do.
　本明細書において「糖尿病白内障」とは、血液中または血漿中のグルコース濃度が持続的に上昇している状態によって特徴づけられる疾患の罹患者において発症している、水晶体の混濁を意図する。一例において、上記疾患は、高血糖症または糖尿病である。一例において、上記糖尿病は、一型糖尿病または二型糖尿病である。上記糖尿病白内障においては、水晶体の皮質または後嚢下に混濁が生じることが多いことが大規模疫学調査で知られているが、混濁の生じる箇所はこれらに限定されない。 As used herein, “diabetic cataract” refers to opacity of the lens that occurs in a patient suffering from a disease that is characterized by a continuously rising glucose concentration in blood or plasma. In one example, the disease is hyperglycemia or diabetes. In one example, the diabetes is type 1 diabetes or type 2 diabetes. In the above-mentioned diabetic cataract, it is known in large-scale epidemiological studies that turbidity often occurs in the cortex or posterior capsule of the lens. However, the location where turbidity occurs is not limited thereto.
　本発明の一実施形態に係る白内障の予防剤または治療剤は、糖尿病白内障の予防または治療を目的として用いられることが好ましい。 The cataract preventive or therapeutic agent according to an embodiment of the present invention is preferably used for the purpose of preventing or treating diabetic cataract.
　［１－２．予防剤］
　本明細書において「予防剤」とは、予防効果をもたらす薬剤を意図する。上記予防効果とは、以下に例示される効果を意図するが、これらに限定されるものではない。
（１）予防剤を投与しなかった場合と比較して、疾患に係る１つ以上の症状の発症を防止する、またはリスクを低減する。
（２）予防剤を投与しなかった場合と比較して、疾患に係る１つ以上の症状の再発を防止する、またはリスクを低減する。
（３）予防剤を投与しなかった場合と比較して、疾患に係る１つ以上の症状の兆候が生じることを防止する、またはリスクを低減する。 [1-2. Preventive agent]
In the present specification, the “prophylactic agent” intends an agent that provides a preventive effect. The preventive effect is intended to be the effect exemplified below, but is not limited thereto.
(1) Preventing the onset of one or more symptoms related to the disease or reducing the risk, compared to the case where no prophylactic agent is administered.
(2) Prevent the recurrence of one or more symptoms related to the disease or reduce the risk as compared to the case where no prophylactic agent is administered.
(3) prevent or reduce the risk of one or more symptoms of the disease as compared to the case where no prophylactic agent is administered.
　なお、上記疾患に係る１つ以上の症状は、全身的なものであってもよいし、局所的なものであってもよい。 Note that the one or more symptoms related to the disease may be systemic or local.
　［１－３．治療剤］
　本明細書において「治療剤」とは、治療効果をもたらす薬剤を意図する。上記治療効果とは、以下に例示される効果を意図するが、これらに限定されるものではない。
（１）治療剤を投与しなかった場合と比較して、疾患に係る１つ以上の症状の重症度を低減する。
（２）治療剤を投与しなかった場合と比較して、疾患に係る１つ以上の症状の重症度の増加、または進行を防止する。
（３）治療剤を投与しなかった場合と比較して、疾患に係る１つ以上の症状の重症度の増加速度、または進行速度を低減する。 [1-3. Therapeutic agent]
As used herein, “therapeutic agent” intends an agent that provides a therapeutic effect. The therapeutic effect is intended to be the effect exemplified below, but is not limited thereto.
(1) Reduce the severity of one or more symptoms associated with the disease as compared to when no therapeutic agent is administered.
(2) Preventing an increase in the severity or progression of one or more symptoms associated with a disease compared to when no therapeutic agent is administered.
(3) Reduce the rate of increase or progression of the severity of one or more symptoms associated with the disease, compared to when no therapeutic agent is administered.
　なお、上記疾患に係る１つ以上の症状は、全身的なものであってもよいし、局所的なものであってもよい。 Note that the one or more symptoms related to the disease may be systemic or local.
　〔２．ＨＡＴ阻害剤〕
　本発明の一態様は、ＨＡＴ阻害剤を有効成分として含有している。本明細書において、ＨＡＴ阻害剤とは、ヒストンアセチル化酵素（Histone Acetyl Transferase：ＨＡＴ）の機能を阻害する物質を意図する。 [2. HAT inhibitor]
One embodiment of the present invention contains a HAT inhibitor as an active ingredient. In this specification, a HAT inhibitor intends the substance which inhibits the function of histone acetylase (Histone Acetyl Transferase: HAT).
　ＨＡＴは、ヒストンに含まれる特定のリジン残基のアミノ基を、アセチル基に置換する。このことにより、ＤＮＡとヒストンとが形成しているクロマチン構造が部分的に緩み、ヒストンがアセチル化された部位近傍の遺伝子が発現しやすくなる。ＨＡＴ阻害剤は、上述の過程を阻害することにより、特定の遺伝子の発現を抑制する結果を生じさせる。したがって、本発明の一実施形態に係る白内障の予防剤または治療剤は、エピジェネティックな遺伝子発現制御に作用していることになる。 HAT replaces the amino group of a specific lysine residue contained in histone with an acetyl group. As a result, the chromatin structure formed by DNA and histone is partially loosened, and the gene in the vicinity of the site where histone is acetylated is easily expressed. A HAT inhibitor causes a result of suppressing the expression of a specific gene by inhibiting the above-described process. Therefore, the preventive or therapeutic agent for cataract according to one embodiment of the present invention acts on epigenetic gene expression control.
　［２－１．ＨＡＴ阻害剤の標的］
　本明細書において、特定のＨＡＴ阻害剤により機能が阻害されるＨＡＴのことを、当該ＨＡＴ阻害剤の「標的」と呼ぶ。ＨＡＴ阻害剤は、標的であるＨＡＴと結合するなどして、「直接的に」ＨＡＴの機能を阻害してよい。一方、ＨＡＴ阻害剤は、ＨＡＴの機能に必要な物質を捕捉するなどして、「間接的に」ＨＡＴの機能を阻害してもよい（この場合、上記ＨＡＴの機能に必要な物質もまた、上記ＨＡＴと同じく「ＨＡＴ阻害剤の標的」と呼ぶ）。すなわち、ＨＡＴ阻害剤の標的は、ＨＡＴである場合もあれば、ＨＡＴでない場合もある。 [2-1. Target of HAT inhibitor]
In the present specification, HAT whose function is inhibited by a specific HAT inhibitor is referred to as a “target” of the HAT inhibitor. A HAT inhibitor may “directly” inhibit HAT function, such as by binding to a target HAT. On the other hand, the HAT inhibitor may inhibit the function of HAT "indirectly" by capturing a substance necessary for the function of HAT (in this case, the substance necessary for the function of HAT is also Like the above HAT, it is called “target of HAT inhibitor”). That is, the target of the HAT inhibitor may be HAT or not HAT.
　一実施形態において、上記ＨＡＴ阻害剤が標的とするＨＡＴは、下表に記載されたＨＡＴ群のうち、１つ以上のサブタイプのＨＡＴでありうる。一実施形態において、上記ＨＡＴ阻害剤が標的とするＨＡＴは、下記表１に記載されたＨＡＴ群のうち、１つ以上のファミリーに属するＨＡＴ群でありうる。 In one embodiment, the HAT targeted by the HAT inhibitor may be one or more subtypes of HAT among the HAT groups listed in the table below. In one embodiment, the HAT targeted by the HAT inhibitor may be a HAT group belonging to one or more families among the HAT groups described in Table 1 below.
Figure JPOXMLDOC01-appb-T000001
 　一実施形態において、上記ＨＡＴ阻害剤が標的とする物質は、ＮＡＴ１０またはＢＲＤ４でありうる。
Figure JPOXMLDOC01-appb-T000001
 In one embodiment, the substance targeted by the HAT inhibitor may be NAT10 or BRD4.
　一実施形態において、上記ＨＡＴ阻害剤の標的は、本明細書においてＨＡＴ阻害剤の標的になりうると記載されている物質、および当業者がＨＡＴ阻害剤の標的と認める物質から選択される、１種類以上である。すなわち、上記ＨＡＴ阻害剤の標的は、１種類のみでもよいし、２種類以上でもよい。また、上記ＨＡＴ阻害剤は、ＨＡＴである物質およびＨＡＴ以外の物質を、共に標的としてもよい。更に、上記ＨＡＴ阻害剤の標的は、上述されている物質を含む複合体であってもよい。 In one embodiment, the target of the HAT inhibitor is selected from substances described herein that can be a target of a HAT inhibitor, and substances recognized by those skilled in the art as a target of a HAT inhibitor. More than types. That is, the target of the HAT inhibitor may be only one type or two or more types. In addition, the HAT inhibitor may target both a substance that is HAT and a substance other than HAT. Furthermore, the target of the HAT inhibitor may be a complex containing the substances described above.
　［２－２．ＨＡＴ阻害剤］
　一実施形態において、上記ＨＡＴ阻害剤は、クルクミンである。上記クルクミンのＩＵＰＡＣ名は(1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione、ＣＡＳ番号は４５８－３７－７、構造式は下式１である。上記クルクミンは、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とする。 [2-2. HAT inhibitor]
In one embodiment, the HAT inhibitor is curcumin. The above IUPAC name of curcumin is (1E, 6E) -1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione, CAS number is 458-37-7, structural formula Is the following formula 1. The curcumin targets the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000002
 　一実施形態において、上記ＨＡＴ阻害剤は、２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサン（別名HAT inhibitor II）である。上記２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサンのＩＵＰＡＣ名は2,6-bis((e)-3-bromo-4-hydroxybenzylidene)cyclohexan、ＣＡＳ番号は９３２７４９－６２－７、構造式は下式２である。上記２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサンは、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とする。
Figure JPOXMLDOC01-appb-C000002
 In one embodiment, the HAT inhibitor is 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane (also known as HAT inhibitor II). The IUPAC name of 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexan, CAS number is 932749- 62-7, the structural formula is the following formula 2. The 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane targets the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000003
 　一実施形態において、上記ＨＡＴ阻害剤は、ＣＴＫ７Ａ（別名HAT inhibitor VII）である。上記ＣＴＫ７ＡのＩＵＰＡＣ名はSodium-4-(3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazol-1-yl)benzoate、ＣＡＳ番号は１２９７２６２－１６－８、構造式は下式３である。上記ＣＴＫ７Ａは、Ｐ３００およびＰＣＡＦを標的とする。
Figure JPOXMLDOC01-appb-C000003
 In one embodiment, the HAT inhibitor is CTK7A (also known as HAT inhibitor VII). The IUPAC name of the above CTK7A is Sodium-4- (3,5-bis (4-hydroxy-3-methoxystyryl) -1H-pyrazol-1-yl) benzoate, CAS number is 1,297262-16-8, and the structural formula is 3. The CTK7A targets P300 and PCAF.
Figure JPOXMLDOC01-appb-C000004
 　一実施形態において、上記ＨＡＴ阻害剤は、Ｅｐｉｇｅｎｅｔｉｃ　Ｍｕｌｔｉｐｌｅ
　Ｌｉｇａｎｄである。上記Ｅｐｉｇｅｎｅｔｉｃ　Ｍｕｌｔｉｐｌｅ　ＬｉｇａｎｄのＩＵＰＡＣ名は3,5-bis(3,5-Dibromo-4-hydroxybenzylidene)-tetrahydro-2H-pyran-4-one、ＣＡＳ番号は１０２０３９９－５２－３、構造式は下式４である。上記Ｅｐｉｇｅｎｅｔｉｃ　Ｍｕｌｔｉｐｌｅ　Ｌｉｇａｎｄは、Ｐ３００を標的とする。
Figure JPOXMLDOC01-appb-C000004
 In one embodiment, the HAT inhibitor is Epigenetic Multiple.
Ligand. The IUPAC name of Epigenetic Multiple Ligand is 3,5-bis (3,5-Dibromo-4-hydroxybenzylidene) -tetrahydro-2H-pyran-4-one, CAS number is 1020399-52-3, and the structural formula is It is. The Epigenetic Multiple Ligand targets P300.
Figure JPOXMLDOC01-appb-C000005
 　一実施形態において、上記ＨＡＴ阻害剤は、ガルシノールである。上記ガルシノールのＩＵＰＡＣ名は3-［(3,4-Dihydroxyphenyl)-hydroxymethylidene］-6,6-dimethyl-5,7-bis(3-methylbut-2-enyl)-1-(5-methyl-2-prop-1-en-2-ylhex-4-enyl)bicyclo［3.3.1］nonane-2,4,9-trione、ＣＡＳ番号は７８８２４－３０－３、構造式は下式５である。上記ガルシノールは、Ｐ３００およびＰＣＡＦを標的とする。
Figure JPOXMLDOC01-appb-C000005
 In one embodiment, the HAT inhibitor is garcinol. The IUPAC name of the above garcinol is 3-[(3,4-Dihydroxyphenyl) -hydroxymethylidene] -6,6-dimethyl-5,7-bis (3-methylbut-2-enyl) -1- (5-methyl-2- prop-1-en-2-ylhex-4-enyl) bicyclo [3.3.1] nonane-2,4,9-trione, CAS number is 78824-30-3, structural formula is the following formula 5. The garcinol targets P300 and PCAF.
Figure JPOXMLDOC01-appb-C000006
 　一実施形態において、上記ＨＡＴ阻害剤は、アナカルド酸である。上記アナカルド酸のＩＵＰＡＣ名は2-hydroxy-6-［(8Z,11Z)-pentadeca-8,11,14-trienyl］benzoic acid、ＣＡＳ番号は１１０３４－７７－８、構造式は下式６である。上記アナカルド酸は、Ｐ３００およびＰＣＡＦを標的とする。
Figure JPOXMLDOC01-appb-C000006
 In one embodiment, the HAT inhibitor is anacardic acid. The IUPAC name of the anacardic acid is 2-hydroxy-6-[(8Z, 11Z) -pentadeca-8,11,14-trienyl] benzoic acid, the CAS number is 11034-77-8, and the structural formula is . The anacardic acid targets P300 and PCAF.
Figure JPOXMLDOC01-appb-C000007
 　一実施形態において、上記ＨＡＴ阻害剤は、ＭＧ１４９である。上記ＭＧ１４９のＩＵＰＡＣ名は2-(4-heptylphenethyl)-6-hydroxybenzoic acid、ＣＡＳ番号は１２４３５８３－８５－８、構造式は下式７である。上記ＭＧ１４９は、ＴＩＰ６０およびＭＯＺを標的とする。
Figure JPOXMLDOC01-appb-C000007
 In one embodiment, the HAT inhibitor is MG149. The IUPAC name of MG149 is 2- (4-heptylphenethyl) -6-hydroxybenzoic acid, the CAS number is 1243583-85-8, and the structural formula is Formula 7. The MG149 targets TIP60 and MOZ.
Figure JPOXMLDOC01-appb-C000008
 　一実施形態において、上記ＨＡＴ阻害剤は、Ｃ６４６である。上記Ｃ６４６のＩＵＰＡＣ名は4-［4-［［5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl］methylene］-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl］benzoic acid、ＣＡＳ番号は３２８９６８－３６－１、構造式は下式８である。上記Ｃ６４６は、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とする。
Figure JPOXMLDOC01-appb-C000008
 In one embodiment, the HAT inhibitor is C646. The IUPAC name of C646 is 4- [4-[[5- (4,5-Dimethyl-2-nitrophenyl) -2-furanyl] methylene] -4,5-dihydro-3-methyl-5-oxo-1H- pyrazol-1-yl] benzoic acid, CAS No. 328968-36-1 and structural formula is Formula 8 below. The C646 targets the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000009
 　一実施形態において、上記ＨＡＴ阻害剤は、ＮＵ９０５６である。上記ＮＵ９０５６のＩＵＰＡＣ名は5-(1,2-Thiazol-5-yldisulfanyl)-1,2-thiazole、ＣＡＳ番号は１４５０６４４－２８－６、構造式は下式９である。上記ＮＵ９０５６は、ＴＩＰ６０を標的とする。
Figure JPOXMLDOC01-appb-C000009
 In one embodiment, the HAT inhibitor is NU9056. The IUPAC name of NU9056 is 5- (1,2-Thiazol-5-yldisulfanyl) -1,2-thiazole, the CAS number is 14450644-28-6, and the structural formula is Formula 9 below. The NU9056 targets TIP60.
Figure JPOXMLDOC01-appb-C000010
 　一実施形態において、上記ＨＡＴ阻害剤は、ＣＰＴＨ２である。上記ＣＰＴＨ２のＩＵＰＡＣ名は2-［4-(4-chlorophenyl)-2-thiazolyl］hydrazone-cyclopentanone, monohydrochloride、ＣＡＳ番号は３５７６４９－９３－５、構造式は下式１０である。上記ＣＰＴＨ２は、ＧＣＮ５を標的とする。
Figure JPOXMLDOC01-appb-C000010
 In one embodiment, the HAT inhibitor is CPTH2. The IUPAC name of CPTH2 is 2- [4- (4-chlorophenyl) -2-thiazolyl] hydrazone-cyclopentanone, monohydrochloride, CAS number is 357649-93-5, and structural formula is the following formula 10. The CPTH2 targets GCN5.
Figure JPOXMLDOC01-appb-C000011
 　一実施形態において、上記ＨＡＴ阻害剤は、５－クロロ－２－（４－ニトロフェニル）－３（２Ｈ）－イソチアゾロンである。上記５－クロロ－２－（４－ニトロフェニル）－３（２Ｈ）－イソチアゾロンのＩＵＰＡＣ名は5-Chloro-2-(4-nitrophenyl)-3(2H)-isothiazolone、ＣＡＳ番号は７４８７７７－４７－１、構造式は下式１１である。上記５－クロロ－２－（４－ニトロフェニル）－３（２Ｈ）－イソチアゾロンは、Ｐ３００およびＰＣＡＦを標的とする。
Figure JPOXMLDOC01-appb-C000011
 In one embodiment, the HAT inhibitor is 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone. The IUPAC name of 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone is 5-Chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone and CAS number is 748777-47- 1. The structural formula is the following formula 11. The 5-chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone targets P300 and PCAF.
Figure JPOXMLDOC01-appb-C000012
 　一実施形態において、上記ＨＡＴ阻害剤は、ブチロラクトン３（別名ＭＢ－３）である。上記ブチロラクトン３のＩＵＰＡＣ名は3-Methylene-4-hydroxycarbonyl-5-(1-propyl)-tetrahydrofuran-2-one、ＣＡＳ番号は７７８６４９－１８－６、構造式は下式１２である。上記ブチロラクトン３は、ＧＣＮ５を標的とする。
Figure JPOXMLDOC01-appb-C000012
 In one embodiment, the HAT inhibitor is butyrolactone 3 (also known as MB-3). The butyrolactone 3 has an IUPAC name of 3-Methylene-4-hydroxycarbonyl-5- (1-propyl) -tetrahydrofuran-2-one, a CAS number of 7786649-18-6, and a structural formula of the following formula 12. The butyrolactone 3 targets GCN5.
Figure JPOXMLDOC01-appb-C000013
 　一実施形態において、上記ＨＡＴ阻害剤は、没食子酸である。上記没食子酸のＩＵＰＡＣ名は3,4,5-trihydroxybenzoic acid、ＣＡＳ番号は１４９－９１－７、構造式は下式１３である。上記没食子酸は、非特異的なＨＡＴ阻害剤である。
Figure JPOXMLDOC01-appb-C000013
 In one embodiment, the HAT inhibitor is gallic acid. The IUPAC name of the gallic acid is 3,4,5-trihydroxybenzoic acid, the CAS number is 149-91-7, and the structural formula is Formula 13. The gallic acid is a non-specific HAT inhibitor.
Figure JPOXMLDOC01-appb-C000014
 　一実施形態において、上記ＨＡＴ阻害剤は、（－）－エピガロカテキンガラートである。上記（－）－エピガロカテキンガラートのＩＵＰＡＣ名は［(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl］ 3,4,5-trihydroxybenzoate、ＣＡＳ番号は９８９－５１－５、構造式は下式１４である。上記（－）－エピガロカテキンガラートは、非特異的なＨＡＴ阻害剤である。
Figure JPOXMLDOC01-appb-C000014
 In one embodiment, the HAT inhibitor is (−)-epigallocatechin gallate. The IUPAC name of the above (−)-epigallocatechin gallate is [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5- trihydroxybenzoate, CAS number is 989-51-5, and structural formula is the following formula 14. The (−)-epigallocatechin gallate is a non-specific HAT inhibitor.
Figure JPOXMLDOC01-appb-C000015
 　一実施形態において、上記ＨＡＴ阻害剤は、ＥＭＬ４２５である。上記ＥＭＬ４２５のＩＵＰＡＣ名は5-［(4-Hydroxy-2,6-dimethylphenyl)methylene］-1,3-bis(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione、ＣＡＳ番号は１６７５８２１－３２－５、構造式は下式１５である。上記ＥＭＬ４２５は、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とする。
Figure JPOXMLDOC01-appb-C000015
 In one embodiment, the HAT inhibitor is EML425. The IUPAC name of the EML425 is 5-[(4-Hydroxy-2,6-dimethylphenyl) methylene] -1,3-bis (phenylmethyl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione, CAS number is 1675821-32-5, the structural formula is the following formula 15. The EML425 targets the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000016
 　一実施形態において、上記ＨＡＴ阻害剤は、Ｌ００２である。上記Ｌ００２のＩＵＰＡＣ名は4-［O-［(4-Methoxyphenyl)sulfonyl］oxime］-2,6-dimethyl-2,5-cyclohexadiene-1,4-dione、ＣＡＳ番号は３２１６９５－５７－２、構造式は下式１６である。上記Ｌ００２は、Ｐ３００を標的とする。
Figure JPOXMLDOC01-appb-C000016
 In one embodiment, the HAT inhibitor is L002. The IUPAC name of L002 is 4- [O-[(4-Methoxyphenyl) sulfonyl] oxime] -2,6-dimethyl-2,5-cyclohexadiene-1,4-dione, CAS number is 321695-57-2, structure The formula is the following formula 16. The above L002 targets P300.
Figure JPOXMLDOC01-appb-C000017
 　一実施形態において、上記ＨＡＴ阻害剤は、ＩＳＯＸ　ＤＵＡＬである。上記ＩＳＯＸ
　ＤＵＡＬのＩＵＰＡＣ名は［3-［4-［2-［5-(Dimethyl-1,2-oxazol-4-yl)-1-［2-(morpholin-4-yl)ethyl］-1H-1,3-benzodiazol-2-yl］ethyl］phenoxy］propyl］dimethylamine、ＣＡＳ番号は登録されておらず、構造式は下式１７である。上記ＩＳＯＸ　ＤＵＡＬは、ＣＢＰおよびＢＲＤ４のブロモドメインを標的とする。
Figure JPOXMLDOC01-appb-C000017
 In one embodiment, the HAT inhibitor is ISOX DUAL. ISOX above
The IUPAC name of DUAL is [3- [4- [2- [5- (Dimethyl-1,2-oxazol-4-yl) -1- [2- (morpholin-4-yl) ethyl] -1H-1, 3-benzodiazol-2-yl] ethyl] phenoxy] propyl] dimethylamine, CAS number is not registered, and the structural formula is the following formula 17. The ISOX DUAL targets the bromodomain of CBP and BRD4.
Figure JPOXMLDOC01-appb-C000018
 　一実施形態において、上記ＨＡＴ阻害剤は、プルンバギンである。上記プルンバギンのＩＵＰＡＣ名は5-Hydroxy-2-methyl-1,4-naphthalened-ione、ＣＡＳ番号は４８１－４２－５、構造式は下式１８である。上記プルンバギンは、Ｐ３００を標的とする。
Figure JPOXMLDOC01-appb-C000018
 In one embodiment, the HAT inhibitor is plumbagin. The IUPAC name of plumbagin is 5-Hydroxy-2-methyl-1,4-naphthalened-ione, CAS number is 481-42-5, and the structural formula is Formula 18. The plum bagin targets P300.
Figure JPOXMLDOC01-appb-C000019
 　一実施形態において、上記ＨＡＴ阻害剤は、ＴＨ１８３４である。上記ＴＨ１８３４のＩＵＰＡＣ名は2-(5-(4-((phenethyl(4-(4-(pyrrolidin-1-ylmethyl)phenoxy)butyl)amino)methyl)phenyl)-2H-tetrazol-2-yl)acetic acid dihydrochloride、ＣＡＳ番号は登録されておらず、構造式は下式１９である。上記ＴＨ１８３４は、ＴＩＰ６０を標的とする。
Figure JPOXMLDOC01-appb-C000019
 In one embodiment, the HAT inhibitor is TH1834. The IUPAC name of TH1834 is 2- (5- (4-((phenethyl (4- (4- (pyrrolidin-1-ylmethyl) phenoxy) butyl) amino) methyl) phenyl) -2H-tetrazol-2-yl) acetic The acid dihydrochloride and CAS number are not registered, and the structural formula is the following formula 19. The TH1834 targets TIP60.
Figure JPOXMLDOC01-appb-C000020
 　一実施形態において、上記ＨＡＴ阻害剤は、ＳＰＶ１０６である。上記ＳＰＶ１０６のＩＵＰＡＣ名は2-Pentadecylidene-Propanedioic acid 1,3-diethyl ester、ＣＡＳ番号は１０３６９３９－３８－４、構造式は下式２０である。上記ＳＰＶ１０６は、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とする。また、上記ＳＰＶ１０６は、ＰＣＡＦのアクチベーターでもある。
Figure JPOXMLDOC01-appb-C000020
 In one embodiment, the HAT inhibitor is SPV106. The IUPAC name of the SPV 106 is 2-Pentadecylidene-Propanedioic acid 1,3-diethyl ester, the CAS number is 1036939-38-4, and the structural formula is Formula 20 below. The SPV 106 targets the P300 / CBP family HAT. The SPV 106 is also a PCAF activator.
Figure JPOXMLDOC01-appb-C000021
 　一実施形態において、上記ＨＡＴ阻害剤は、Ｗｉｎｄｏｒｐｈｅｎである。上記ＷｉｎｄｏｒｐｈｅｎのＩＵＰＡＣ名は(E) & (Z)-3-Chloro-2,3-bis(4-methoxyphenyl)acrylaldehyde、ＣＡＳ番号は１９８８１－７０－０、構造式は下式２１である。上記Ｗｉｎｄｏｒｐｈｅｎは、非特異的なＨＡＴ阻害剤である。
Figure JPOXMLDOC01-appb-C000021
 In one embodiment, the HAT inhibitor is Windorphen. The IUPAC name of Windorphen is (E) & (Z) -3-Chloro-2,3-bis (4-methoxyphenyl) acrylaldehyde, the CAS number is 19881-70-0, and the structural formula is Formula 21 below. Windorphen is a non-specific HAT inhibitor.
Figure JPOXMLDOC01-appb-C000022
 　一実施形態において、上記ＨＡＴ阻害剤は、ケトミンである。上記ケトミンのＩＵＰＡＣ名は2,3S,5aR,6,10bS,11-hexahydro-3-(hydroxymethyl)-10b-［(1S,4S)-3-［［4-(hydroxymethyl)-5,7-dimethyl-6,8-dioxo-2,3-dithia-5,7-diazabicyclo［2.2.2］oct-1-yl］methyl］-1H-indol-1-yl］-2-methyl-3,11aS-epidithio-11aH-pyrazino［1',2':1,5］pyrrolo［2,3-b］indole-1,4-dione、ＣＡＳ番号は１４０３－３６－７、構造式は下式２２である。上記ケトミンは、Ｈ１Ｆ１α／Ｐ３００複合体のＴＡＺ１ドメインを標的とする。
Figure JPOXMLDOC01-appb-C000022
 In one embodiment, the HAT inhibitor is ketomin. The IUPAC name of ketomin is 2,3S, 5aR, 6,10bS, 11-hexahydro-3- (hydroxymethyl) -10b-[(1S, 4S) -3-[[4- (hydroxymethyl) -5,7-dimethyl -6,8-dioxo-2,3-dithia-5,7-diazabicyclo [2.2.2] oct-1-yl] methyl] -1H-indol-1-yl] -2-methyl-3,11aS-epidithio -11aH-pyrazino [1 ′, 2 ′: 1,5] pyrrolo [2,3-b] indole-1,4-dione, CAS number is 1403-36-7, and structural formula is the following formula 22. The ketomin targets the TAZ1 domain of the H1F1α / P300 complex.
Figure JPOXMLDOC01-appb-C000023
 　一実施形態において、上記ＨＡＴ阻害剤は、Ｒｅｍｏｄｅｌｉｎである。上記ＲｅｍｏｄｅｌｉｎのＩＵＰＡＣ名は4-［2-(2-cyclopentylidenehydrazinyl)-1,3-thiazol-4-yl］benzonitrile;hydrobromide、ＣＡＳ番号は１６２２９２１－１５－６、構造式は下式２３である。上記Ｒｅｍｏｄｅｌｉｎは、ＮＡＴ１０を標的とする。
Figure JPOXMLDOC01-appb-C000023
 In one embodiment, the HAT inhibitor is Remodelin. The IUPAC name of Remodelin is 4- [2- (2-cyclopentylidenehydrazinyl) -1,3-thiazol-4-yl] benzonitrile; hydrobromide, CAS number is 1622921-15-6, and the structural formula is Formula 23 below. The above Remodelin targets NAT10.
Figure JPOXMLDOC01-appb-C000024
 　一実施形態において、上記ＨＡＴ阻害剤は、エンベリンである。上記エンベリンのＩＵＰＡＣ名は2,5-Dihydroxy-3-undecyl-1,4-benzoquinone、ＣＡＳ番号は５５０－２４－３、構造式は下式２４である。上記エンベリンは、ＰＣＡＦを標的とする。
Figure JPOXMLDOC01-appb-C000024
 In one embodiment, the HAT inhibitor is envelin. The IUPAC name of the above embellin is 2,5-Dihydroxy-3-undecyl-1,4-benzoquinone, the CAS number is 550-24-3, and the structural formula is Formula 24 below. The envelin targets PCAF.
Figure JPOXMLDOC01-appb-C000025
 　一実施形態において、上記ＨＡＴ阻害剤は、Ｉｓｃｈｅｍｉｎである。上記ＩｓｃｈｅｍｉｎのＩＵＰＡＣ名は5-［(1E)-2-(2-Amino-4-hydroxy-5-methylphenyl)diazenyl］-2,4-dimethylbenzenesulfonic acid sodium salt、ＣＡＳ番号は１３５７０５９－００－７、構造式は下式２５である。上記Ｉｓｃｈｅｍｉｎは、Ｐ３００／ＣＢＰファミリーのＨＡＴのブロモドメインを標的とする。
Figure JPOXMLDOC01-appb-C000025
 In one embodiment, the HAT inhibitor is Ischemin. The IUPAC name of the above Ischemin is 5-[(1E) -2- (2-Amino-4-hydroxy-5-methylphenyl) diazenyl] -2,4-dimethylbenzenesulfonic acid sodium salt, CAS number is 1357059-00-7, structure The formula is the following formula 25. The Ischemin targets the bromodomain of the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000026
 　一実施形態において、上記ＨＡＴ阻害剤は、ＣＢＰ３０である。上記ＣＢＰ３０のＩＵＰＡＣ名は8-(3-chloro-4-methoxy-phenethyl)-4-(3,5-dimethyl-isoxazol-4-yl)-9-(2-(morpholin-4-yl)-propyl)-7,9-diaza-bicyclo［4.3.0］nona-1(6),2,4,7-tetraene、ＣＡＳ番号は１６１３６９５－１４－９、構造式は下式２６である。上記ＣＢＰ３０は、Ｐ３００／ＣＢＰファミリーのＨＡＴのブロモドメインを標的とする。
Figure JPOXMLDOC01-appb-C000026
 In one embodiment, the HAT inhibitor is CBP30. The IUPAC name of the CBP30 is 8- (3-chloro-4-methoxy-phenethyl) -4- (3,5-dimethyl-isoxazol-4-yl) -9- (2- (morpholin-4-yl) -propyl ) -7,9-diaza-bicyclo [4.3.0] nona-1 (6), 2,4,7-tetraene, CAS number is 1613695-14-9, structural formula is the following formula 26. The CBP30 targets the bromodomain of the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000027
 　一実施形態において、上記ＨＡＴ阻害剤は、ＫＧ５０１（別名ナフトールＡＳ－Ｅホスフェート）である。上記ＫＧ５０１のＩＵＰＡＣ名は3-［(4-chlorophenyl)carbamoyl］-2-naphthyl dihydrogen phosphate; N-(4-Chlorophenyl)-3-(phosphonooxy)naphthalene-2-carboxamide、ＣＡＳ番号は１８２２８－１７－６、構造式は下式２７である。上記ＫＧ５０１は、Ｐ３００／ＣＢＰファミリーのＨＡＴのＫＩＸドメインを標的とする。
Figure JPOXMLDOC01-appb-C000027
 In one embodiment, the HAT inhibitor is KG501 (also known as naphthol AS-E phosphate). The IUPAC name of the above KG501 is 3-[(4-chlorophenyl) carbamoyl] -2-naphthyl dihydrogen phosphate; N- (4-Chlorophenyl) -3- (phosphonooxy) naphthalene-2-carboxamide, CAS number is 18228-17-6 The structural formula is the following formula 27. The KG501 targets the KIX domain of the P300 / CBP family HAT.
Figure JPOXMLDOC01-appb-C000028
 　上述した物質のうち、２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサン、ＣＴＫ７Ａ、ガルシノール、アナカルド酸、ＭＧ１４９、没食子酸、（－）－エピガロカテキンガラート、プルンバギンおよびエンベリンは、ポリフェノール由来の化合物である。
Figure JPOXMLDOC01-appb-C000028
 Among the substances mentioned above, 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, garcinol, anacardic acid, MG149, gallic acid, (−)-epigallocatechin gallate, plumbagin And embellin is a compound derived from polyphenol.
　上述した物質のうち、ＣＴＫ７Ａ、アナカルド酸、ＭＧ１４９、Ｃ６４６、没食子酸、（－）－エピガロカテキンガラートおよびプルンバギンは、安息香酸誘導体である。 Among the above-mentioned substances, CTK7A, anacardic acid, MG149, C646, gallic acid, (−)-epigallocatechin gallate and plumbagin are benzoic acid derivatives.
　上述した物質のうち、ＣＴＫ７Ａ、Ｃ６４６、ＣＰＴＨ２、ＩＳＯＸ　ＤＵＡＬ、ＴＨ１８３４およびＲｅｍｏｄｅｌｉｎは、構造中にヘテロ環を含んでいる。 Among the substances described above, CTK7A, C646, CPTH2, ISOX DUAL, TH1834, and Remodelin contain a heterocycle in the structure.
　上述した物質のうち、２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサン、ブチロラクトン３、ＳＰＶ１０６、Ｗｉｎｄｏｒｐｈｅｎは、α－β不飽和カルボニル化合物である。 Among the substances mentioned above, 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, butyrolactone 3, SPV106, and Windorphen are α-β unsaturated carbonyl compounds.
　一実施形態において、上記ＨＡＴ阻害剤は、上述した物質の誘導体または塩であってよい。上述した物質の誘導体または塩をＨＡＴ阻害剤として用いることにより、（１）白内障の予防効果または治療効果が増大する、（２）物質の人体に対する安全性が増大する、（３）製剤に当たって扱いやすい物性を得る、などの効果を付与しうる。 In one embodiment, the HAT inhibitor may be a derivative or salt of the substances described above. By using a derivative or salt of the above-mentioned substance as a HAT inhibitor, (1) the preventive or therapeutic effect of cataract is increased, (2) the safety of the substance to the human body is increased, and (3) the preparation is easy to handle. Effects such as obtaining physical properties can be imparted.
　本明細書において、「誘導体」とは、特定の化合物に対して、当該化合物の分子内の一部が、他の官能基または他の原子と置換されることにより生じる化合物群を意図する。 In the present specification, “derivative” means a group of compounds produced by substituting a part of the compound in the molecule with another functional group or another atom for a specific compound.
　上記他の官能基の例としては、アルキル基、アルコキシ基、アルキルチオ基、アリール基、アリールオキシ基、アリールチオ基、アリールアルキル基、アリールアルコキシ基、アリールアルキルチオ基、アリールアルケニル基、アリールアルキニル基、アリル基、アミノ基、置換アミノ基、シリル基、置換シリル基、シリルオキシ基、置換シリルオキシ基、アリールスルフォニルオキシ基、アルキルスルフォニルオキシ基、ニトロ基などが挙げられる。上記他の原子の例としては、炭素原子、水素原子、酸素原子、窒素原子、硫黄原子、リン原子、ハロゲン原子などが挙げられる。 Examples of the other functional groups include alkyl groups, alkoxy groups, alkylthio groups, aryl groups, aryloxy groups, arylthio groups, arylalkyl groups, arylalkoxy groups, arylalkylthio groups, arylalkenyl groups, arylalkynyl groups, allyls. Group, amino group, substituted amino group, silyl group, substituted silyl group, silyloxy group, substituted silyloxy group, arylsulfonyloxy group, alkylsulfonyloxy group, nitro group and the like. Examples of the other atoms include a carbon atom, a hydrogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, and a halogen atom.
　本明細書において、「塩」とは、医薬品として被験体に投与することが生理学的に許容されうる塩であるならば、限定されない。塩の例としては、アルカリ金属塩（カリウム塩など）、アルカリ土類金属塩（カルシウム塩、マグネシウム塩など）、アンモニウム塩、有機塩基塩（トリメチルアミン塩、トリエチルアミン塩、ピリジン塩、ピコリン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’－ジベンジルエチレンジアミン塩など）、有機酸塩（酢酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、蟻酸塩、トルエンスルホン酸塩、トリフルオロ酢酸塩など）、無機酸塩（塩酸塩、臭化水素酸塩、硫酸塩、燐酸塩など）を挙げられる。 In the present specification, the “salt” is not limited as long as it is a salt that is physiologically acceptable to be administered to a subject as a pharmaceutical product. Examples of salts include alkali metal salts (potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamines). Salt, N, N'-dibenzylethylenediamine salt), organic acid salt (acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate And inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.).
　ＨＡＴ阻害剤の例として上述した物質の誘導体または塩は、公知の手法により製造することができる。 Derivatives or salts of the substances described above as examples of HAT inhibitors can be produced by known methods.
　〔３．白内障の予防剤または治療剤〕
　［３－１．投与形態および剤型］
　本発明の一実施形態に係る白内障の予防剤または治療剤は、被験体に対して投与される。一実施形態において、上記被験体はヒトである。他の実施形態において、上記被験体は、ヒト以外の動物である。上記ヒト以外の動物の例としては、ヒト以外の哺乳類（ウシ、ブタ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、ウサギ、マウス、ラットなど）が挙げられる。 [3. (Prevention or treatment of cataract)
[3-1. Dosage form and dosage form]
The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention is administered to a subject. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human animal. Examples of the non-human animals include mammals other than humans (cow, pig, sheep, goat, horse, dog, cat, rabbit, mouse, rat, etc.).
　本発明の一実施形態に係る白内障の予防剤または治療剤は、任意の投与経路によって被験体に投与されうる。上記投与経路の例としては、経口投与、非経口投与、経皮投与、経粘膜投与、経静脈投与が挙げられる。したがって、上記白内障の予防剤または治療剤の剤型は、内服薬、外用薬、注射剤、坐剤、吸入剤、点眼剤などでありうる。 The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention can be administered to a subject by any route of administration. Examples of the administration route include oral administration, parenteral administration, transdermal administration, transmucosal administration, and intravenous administration. Therefore, the dosage form of the prophylactic or therapeutic agent for cataract may be an internal medicine, an external medicine, an injection, a suppository, an inhalant, an eye drop and the like.
　上述した投与経路の中でも、非経口投与が好ましく、点眼投与、結膜能内投与、硝子体内投与、結膜下投与、テノン嚢下投与がより好ましく、点眼投与が更に好ましい。したがって、上述した剤型の中でも、点眼剤または注射剤が好ましく、点眼剤がより好ましい。点眼剤が好ましい理由としては、有効成分を水晶体に送達するまでの経路が短いこと、他の器官を刺激しにくいこと、侵襲がほとんどないこと、全身への影響が小さいこと（点眼後の涙点圧迫によりさらに全身への影響を抑えることができる）、投与が簡便であること、反復投与が可能であること、患者が自己管理できることなどが挙げられる。このため、白内障の予防効果または治療効果を、より迅速にすること、より増大させることなどが期待できる。 Among the administration routes described above, parenteral administration is preferred, ophthalmic administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, and subtenon administration are more preferred, and ophthalmic administration is even more preferred. Accordingly, among the above-mentioned dosage forms, eye drops or injections are preferable, and eye drops are more preferable. The reasons why ophthalmic solutions are preferable are that the route until the active ingredient is delivered to the lens is short, that other organs are difficult to irritate, that there is little invasion, and that the effect on the whole body is small (the punctum after instillation) The effects on the whole body can be further suppressed by compression), administration is simple, repeated administration is possible, and patients can be self-administered. For this reason, it can be expected that the effect of preventing or treating cataract is made quicker or increased.
　［３－２．含有成分］
　本発明の一実施形態に係る白内障の予防剤または治療剤は、有効成分としてＨＡＴ阻害剤を含んでいる。本明細書において、「有効成分」とは、１つ以上の症状に対して予防効果または治療効果をもたらすことのできる物質を意図する。 [3-2. Ingredients]
The preventive or therapeutic agent for cataract according to one embodiment of the present invention contains a HAT inhibitor as an active ingredient. As used herein, “active ingredient” intends a substance that can provide a prophylactic or therapeutic effect against one or more symptoms.
　本発明の一実施形態に係る白内障の予防剤または治療剤は、１種類のＨＡＴ阻害剤のみを含んでいてもよいし、２種類以上のＨＡＴ阻害剤を組み合わせて含んでいてもよい。２種類以上のＨＡＴ阻害剤を組み合わせることにより、個々のＨＡＴ阻害剤の効果からは予想できない、相乗的な効果を得ることができる。 The preventive or therapeutic agent for cataract according to one embodiment of the present invention may contain only one type of HAT inhibitor, or may contain a combination of two or more types of HAT inhibitors. By combining two or more HAT inhibitors, a synergistic effect that cannot be predicted from the effects of the individual HAT inhibitors can be obtained.
　このような相乗的な効果が得られるＨＡＴ阻害剤の組み合わせの一例としては、（１）ＣＢＰ３０とＣＰＴＨ２との組み合わせ、および（２）Ｃ６４６とＣＰＴＨ２との組み合わせ、が挙げられる。 Examples of combinations of HAT inhibitors that can provide such a synergistic effect include (1) a combination of CBP30 and CPTH2, and (2) a combination of C646 and CPTH2.
　本発明の一実施形態に係る白内障の予防剤または治療剤に含まれるＨＡＴ阻害剤の濃度は、当該ＨＡＴ阻害剤の種類、並びに選択される投与経路および剤型などによって異なる。一例において、上記ＨＡＴ阻害剤の濃度の下限は、０．００１μＭ以上、０．００２μＭ以上、０．００５μＭ以上、０．０１μＭ以上、０．０２μＭ以上、０．０５μＭ以上、０．１μＭ以上、０．２μＭ以上、０．５μＭ以上、１μＭ以上、２μＭ以上、３μＭ以上、４μＭ以上、５μＭ以上、６μＭ以上、７μＭ以上、８μＭ以上、９μＭ以上、１０μＭ以上、２０μＭ以上、３０μＭ以上、４０μＭ以上、５０μＭ以上、６０μＭ以上、７０μＭ以上、８０μＭ以上、９０μＭ以上、１００μＭ以上、２００μＭ以上、３００μＭ以上、４００μＭ以上または５００μＭ以上である。 The concentration of the HAT inhibitor contained in the preventive or therapeutic agent for cataract according to one embodiment of the present invention varies depending on the type of the HAT inhibitor, the administration route and the dosage form selected. In one example, the lower limit of the concentration of the HAT inhibitor is 0.001 μM or more, 0.002 μM or more, 0.005 μM or more, 0.01 μM or more, 0.02 μM or more, 0.05 μM or more, 0.1 μM or more, 0. 2 μM or more, 0.5 μM or more, 1 μM or more, 2 μM or more, 3 μM or more, 4 μM or more, 6 μM or more, 7 μM or more, 8 μM or more, 9 μM or more, 10 μM or more, 20 μM or more, 30 μM or more, 40 μM or more, 50 μM or more, It is 60 μM or more, 70 μM or more, 80 μM or more, 90 μM or more, 100 μM or more, 200 μM or more, 300 μM or more, 400 μM or more, or 500 μM or more.
　一例において、上記ＨＡＴ阻害剤の濃度の上限は、０．０１μＭ以下、０．０２μＭ以下、０．０５μＭ以下、０．１μＭ以下、０．２μＭ以下、０．５μＭ以下、１μＭ以下、２μＭ以下、３μＭ以下、４μＭ以下、５μＭ以下、６μＭ以下、７μＭ以下、８μＭ以下、９μＭ以下、１０μＭ以下、２０μＭ以下、３０μＭ以下、４０μＭ以下、５０μＭ以下、６０μＭ以下、７０μＭ以下、８０μＭ以下、９０μＭ以下、１００μＭ以下、２００μＭ以下、３００μＭ以下、４００μＭ以下、５００μＭ以下、１０００μＭ以下、２０００μＭ以下または５０００μＭ以下である。 In one example, the upper limit of the concentration of the HAT inhibitor is 0.01 μM or less, 0.02 μM or less, 0.05 μM or less, 0.1 μM or less, 0.2 μM or less, 0.5 μM or less, 1 μM or less, 2 μM or less, 3 μM 4 μM or less, 5 μM or less, 6 μM or less, 7 μM or less, 8 μM or less, 9 μM or less, 10 μM or less, 20 μM or less, 30 μM or less, 40 μM or less, 50 μM or less, 60 μM or less, 70 μM or less, 80 μM or less, 90 μM or less, 100 μM or less, 200 μM or less, 300 μM or less, 400 μM or less, 500 μM or less, 1000 μM or less, 2000 μM or less, or 5000 μM or less.
　一例において、上記ＨＡＴ阻害剤の濃度は、０．００１～０．０１μＭ、０．００２～０．０２μＭ、０．００５～０．０５μＭ、０．０１～０．１μＭ、０．０２～０．２μＭ、０．０５～０．５μＭ、０．１～１μＭ、０．２～２μＭ、０．３～３μＭ、０．４～４μＭ、０．５～５μＭ、０．６～６μＭ、０．７～７μＭ、０．８～８μＭ、０．９～９μＭ、１～１０μＭ、２～２０μＭ、３～３０μＭ、４～４０μＭ、５～５０μＭ、６～６０μＭ、７～７０μＭ、８～８０μＭ、９～９０μＭ、１０～１００μＭ、２０～２００μＭ、３０～３００μＭ、４０～４００μＭ、５０～５００μＭ、６０～６００μＭ、７０～７００μＭ、８０～８００μＭ、９０～９００μＭ、１００～１０００μＭ、２００～２０００μＭまたは５００～５０００μＭである。 In one example, the concentration of the HAT inhibitor is 0.001 to 0.01 μM, 0.002 to 0.02 μM, 0.005 to 0.05 μM, 0.01 to 0.1 μM, 0.02 to 0.2 μM. 0.05 to 0.5 μM, 0.1 to 1 μM, 0.2 to 2 μM, 0.3 to 3 μM, 0.4 to 4 μM, 0.5 to 5 μM, 0.6 to 6 μM, 0.7 to 7 μM 0.8-8 μM, 0.9-9 μM, 1-10 μM, 2-20 μM, 3-30 μM, 4-40 μM, 5-50 μM, 6-60 μM, 7-70 μM, 8-80 μM, 9-90 μM, 10 -100 μM, 20-200 μM, 30-300 μM, 40-400 μM, 50-500 μM, 60-600 μM, 70-700 μM, 80-800 μM, 90-900 μM, 100-1000 μM, 200-2000 μM, or 500-5000 μM. .
　本発明の一実施形態に係る白内障の予防剤または治療剤は、ＨＡＴ阻害剤以外の成分を含有していてよい。上記ＨＡＴ阻害剤以外の成分は、有効成分であってもよいし、有効成分でなくともよい。 The preventive or therapeutic agent for cataract according to one embodiment of the present invention may contain components other than the HAT inhibitor. Ingredients other than the HAT inhibitor may be active ingredients or not active ingredients.
　上記ＨＡＴ阻害剤以外の成分のうち、有効成分は、白内障に関連する症状（白内障の症状、白内障の合併症の症状など）に対する有効成分であってもよいし、白内障に関連しない症状に対する有効成分であってもよい。 Among the ingredients other than the HAT inhibitor, the active ingredient may be an active ingredient for symptoms related to cataract (symptoms of cataracts, complications of cataracts, etc.), or an active ingredient for symptoms not related to cataracts It may be.
　上記ＨＡＴ阻害剤以外の成分のうち、有効成分でない成分の類型としては、緩衝剤、ｐＨ調整剤、等張化剤、防腐剤、抗酸化剤、高分子量重合体、賦形剤、担体、希釈剤、溶媒、可溶化剤、安定剤、充填剤、結合剤、界面活性剤、安定化剤などが挙げられる。 Among the components other than the HAT inhibitor, the types of components that are not active components include buffers, pH adjusters, tonicity agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, and dilutions. Agents, solvents, solubilizers, stabilizers, fillers, binders, surfactants, stabilizers and the like.
　上記緩衝剤の例としては、リン酸またはリン酸塩、ホウ酸またはホウ酸塩、クエン酸またはクエン酸塩、酢酸または酢酸塩、炭酸または炭酸塩、酒石酸または酒石酸塩、ε－アミノカプロン酸、トロメタモールなどが挙げられる。上記リン酸塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウムなどが挙げられる。上記ホウ酸塩としては、ホウ砂、ホウ酸ナトリウム、ホウ酸カリウムなどが挙げられる。上記クエン酸塩としては、クエン酸ナトリウム、クエン酸二ナトリウム、クエン酸三ナトリウムなどが挙げられる。上記酢酸塩としては、酢酸ナトリウム、酢酸カリウムなどが挙げられる。上記炭酸塩としては、炭酸ナトリウム、炭酸水素ナトリウムなどが挙げられる。上記酒石酸塩としては、酒石酸ナトリウム、酒石酸カリウムなどが挙げられる。 Examples of the buffer include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonic acid or carbonate, tartaric acid or tartrate, ε-aminocaproic acid, trometamol Etc. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. Examples of the borate include borax, sodium borate, and potassium borate. Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate. Examples of the tartrate salt include sodium tartrate and potassium tartrate.
　ｐＨ調整剤の例としては、塩酸、リン酸、クエン酸、酢酸、水酸化ナトリウム、水酸化カリウムなどが挙げられる。 Examples of pH adjusting agents include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide and the like.
　上記等張化剤の例としては、イオン性等張化剤（塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウムなど）、非イオン性等張化剤（グリセリン、プロピレングリコール、ソルビトール、マンニトールなど）が挙げられる。 Examples of the tonicity agent include ionic tonicity agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and nonionic tonicity agents (glycerin, propylene glycol, sorbitol, mannitol, etc.). Can be mentioned.
　上記防腐剤の例としては、ベンザルコニウム塩化物、ベンザルコニウム臭化物、ベンゼトニウム塩化物、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノールなどが挙げられる。 Examples of the preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.
　上記抗酸化剤の例としては、アスコルビン酸、トコフェノール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウムなどが挙げられる。 Examples of the antioxidant include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
　上記高分子量重合体の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール、アテロコラーゲンなどが挙げられる。 Examples of the high molecular weight polymer include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, atelocollagen and the like.
　特に、アテロコラーゲンを高分子量重合体として添加することは、ＨＡＴ阻害剤の吸収率が上がるため、好ましい。 In particular, it is preferable to add atelocollagen as a high molecular weight polymer because the absorption rate of the HAT inhibitor is increased.
　本発明の一実施形態に係る白内障の予防剤または治療剤は、上に例示した以外にも、当業者に知られている有効成分および／または医薬品用添加剤を含んでいてよい。 The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention may contain an active ingredient and / or a pharmaceutical additive known to those skilled in the art, other than those exemplified above.
　［３－３．製剤および処方］
　ＨＡＴ阻害剤および上に例示されているＨＡＴ阻害剤以外の成分を原料として、公知の手法により、本発明の一実施形態に係る白内障の予防剤または治療剤が製剤できる。 [3-3. Formulation and prescription]
The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention can be formulated by a known technique using ingredients other than the HAT inhibitor and the HAT inhibitors exemplified above as raw materials.
　本発明の一実施形態に係る白内障の予防剤または治療剤を点眼剤として投与する場合、所望の効果が得られるならば、投与量に制限はない。 When the prophylactic or therapeutic agent for cataract according to one embodiment of the present invention is administered as an eye drop, the dose is not limited as long as a desired effect is obtained.
　本発明の一実施形態に係る白内障の予防剤または治療剤を点眼剤として投与する場合、所望の効果が得られるならば、投与間隔に制限はない。上記投与間隔は、通常１時間～６箇月間に１回であり、好ましくは１時間に１回、２時間に１回、３時間に１回、６時間に１回、１２時間に１回、１日間に１回、２日間に１回、３日間に１回、４日間に１回、５日間に１回、６日間に１回、１週間に１回、２週間に１回、３週間に１回、１箇月間に１回、２箇月間に１回、３箇月間に１回、４箇月間に１回、５箇月間に１回、６箇月間に１回であり、より好ましくは少なくとも１日に１回、少なくとも２日間に１回、少なくとも３日間に１回、少なくとも４日間に１回、少なくとも５日間に１回、少なくとも６日間に１回、少なくとも１週間に１回である。 When the prophylactic or therapeutic agent for cataract according to one embodiment of the present invention is administered as an eye drop, the administration interval is not limited as long as a desired effect is obtained. The administration interval is usually once every 1 hour to 6 months, preferably once per hour, once every 2 hours, once every 3 hours, once every 6 hours, once every 12 hours, Once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, three weeks 1 time, 1 time in 1 month, 1 time in 2 months, 1 time in 3 months, 1 time in 4 months, 1 time in 5 months, 1 time in 6 months, more preferably At least once a day, at least once every two days, at least once every three days, at least once every four days, at least once every five days, at least once every six days, at least once a week is there.
　本発明の一実施形態に係る白内障の予防剤または治療剤を、白内障および／または他の疾患を予防または治療するための薬剤と併用して処方してもよい。 The cataract preventive or therapeutic agent according to one embodiment of the present invention may be prescribed in combination with a drug for preventing or treating cataract and / or other diseases.
　〔４．作用機序〕
　以下、図１に基づいて、本発明の一実施形態に係る白内障の予防剤または治療剤の推定上の作用機序を説明する。なお、以下に説明されるのは作用機序の例示であり、ＨＡＴ阻害剤を含む白内障の予防剤または治療剤の、他の作用機序を排除するものではない。 [4. Mechanism of action〕
Hereinafter, based on FIG. 1, the presumed mechanism of action of the preventive or therapeutic agent for cataract according to one embodiment of the present invention will be described. In addition, what is demonstrated below is an illustration of an action mechanism and does not exclude the other action mechanism of the preventive agent or therapeutic agent of a cataract containing a HAT inhibitor.
　図１の（ａ）は、本発明の一実施形態に係る白内障の予防剤または治療剤の作用機序である。この作用機序は、アポトーシス関連遺伝子Ｐ５３の上流に位置するＰＬＫ３の発現を、ＨＡＴ阻害剤によって抑制するモデルである。 FIG. 1 (a) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to one embodiment of the present invention. This mechanism of action is a model in which the expression of PLK3 located upstream of the apoptosis-related gene P53 is suppressed by a HAT inhibitor.
　ＨＡＴ阻害剤を投与しない場合は、ＨＡＴの機能によりＰ５３が活性化し、水晶体上皮細胞のアポトーシスが誘導される。このことにより、水晶体上皮細胞を通した物質の輸送、および水晶体上皮細胞層から水晶体皮質への細胞の供給が妨げられ、水晶体皮質の恒常性が変化する。すると、従前は水晶体内部の水分に溶解していたタンパク質が析出し、混濁が発生する。図１の（ａ）に示されている作用機序では、ＨＡＴ阻害剤によってＨＡＴ（例えば、［２－１］に記載の物質）の機能が阻害されることにより、ＰＬＫ３の発現が抑制され、結果的に白内障を予防または治療している。なお、ヒストン脱アセチル化酵素（ＨＤＡＣ）阻害剤を投与した場合は、逆の作用機序により、白内障の進行が促進されると考えられる。 When no HAT inhibitor is administered, P53 is activated by the function of HAT, and apoptosis of lens epithelial cells is induced. This impedes the transport of substances through the lens epithelial cells and the supply of cells from the lens epithelial cell layer to the lens cortex, thereby altering the lens cortex homeostasis. Then, the protein that was previously dissolved in the water inside the lens is precipitated and turbidity occurs. In the action mechanism shown in FIG. 1 (a), the expression of PLK3 is suppressed by inhibiting the function of HAT (for example, the substance described in [2-1]) by a HAT inhibitor, As a result, cataract is prevented or treated. When a histone deacetylase (HDAC) inhibitor is administered, the progression of cataract is considered to be promoted by the reverse mechanism of action.
　図１の（ｂ）は、本発明の他の実施形態に係る白内障の予防剤または治療剤の作用機序である。この作用機序は、ＡＬＤＨ１Ａ１の発現を、ＨＡＴ阻害剤によって促進するモデルである。 FIG. 1 (b) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to another embodiment of the present invention. This mechanism of action is a model in which ALDH1A1 expression is promoted by HAT inhibitors.
　ＨＡＴ阻害剤を投与しない場合は、ＨＡＴの機能によりＡＬＤＨ１Ａ１が抑制され、したがってＡＬＤＨ１Ａ１の機能であるアルデヒド蓄積の抑制が抑制される。結果として水晶体内にアルデヒドが蓄積され、アルデヒドにより変質したタンパク質が蓄積して、混濁が生じる。図１の（ｂ）に示されている作用機序では、ＨＡＴ阻害剤によってＨＡＴ（例えば、［２－１］に記載の物質）の機能が阻害されることにより、ＡＬＤＨ１Ａ１の発現が促進され、結果的に白内障を予防または治療している。なお、ＨＤＡＣ阻害剤を投与した場合は、逆の作用機序（ＡＬＤＨ１Ａ１が抑制され、したがってＡＬＤＨ１Ａ１の機能であるアルデヒド蓄積の抑制が抑制される）により、白内障の進行が促進されると考えられる。 When no HAT inhibitor is administered, ALDH1A1 is suppressed by the function of HAT, and thus suppression of aldehyde accumulation, which is a function of ALDH1A1, is suppressed. As a result, aldehyde accumulates in the lens, and proteins altered by the aldehyde accumulate, resulting in turbidity. In the mechanism of action shown in FIG. 1 (b), the expression of ALDH1A1 is promoted by inhibiting the function of HAT (for example, the substance described in [2-1]) by the HAT inhibitor, As a result, cataract is prevented or treated. When an HDAC inhibitor is administered, it is considered that progression of cataract is promoted by the reverse action mechanism (ALDH1A1 is suppressed, and thus suppression of aldehyde accumulation which is a function of ALDH1A1 is suppressed).
　図１の（ｃ）は、本発明のさらに他の実施形態に係る白内障の予防剤または治療剤の作用機序である。この作用機序は、ＧＪＡ１発現が、ＨＡＴ阻害剤によって促進されるモデルである。 FIG. 1 (c) shows the mechanism of action of a prophylactic or therapeutic agent for cataract according to still another embodiment of the present invention. This mechanism of action is a model in which GJA1 expression is promoted by HAT inhibitors.
　ＨＡＴ阻害剤を投与しない場合は、ＨＡＴのＧＪＡ１を活性化する機能が抑制され、水晶体上皮細胞の細胞間接着が低下する。このことにより、水晶体に水分が取り込まれ、浸透圧上昇に伴い混濁が発生する。図１の（ｃ）に示されている作用機序では、ＨＡＴ阻害剤によってＨＡＴ（例えば、［２－１］に記載の物質）の機能が促進されることにより、ＧＪＡ１の発現が促進され、結果的に白内障を予防または治療している。なお、ヒストン脱アセチル化酵素（ＨＤＡＣ）阻害剤を投与した場合は、逆の作用機序により、白内障の進行が促進されると考えられる。このような作用機序を有するＨＡＴ阻害剤の例としては、アナカルド酸が挙げられる。 When no HAT inhibitor is administered, the function of activating GJA1 in HAT is suppressed, and the cell-cell adhesion of lens epithelial cells is reduced. As a result, moisture is taken into the crystalline lens and turbidity occurs as the osmotic pressure increases. In the mechanism of action shown in FIG. 1 (c), the expression of GJA1 is promoted by promoting the function of HAT (for example, the substance described in [2-1]) by the HAT inhibitor, As a result, cataract is prevented or treated. When a histone deacetylase (HDAC) inhibitor is administered, the progression of cataract is considered to be promoted by the reverse mechanism of action. An example of a HAT inhibitor having such a mechanism of action is anacardic acid.
　このように、ＨＡＴ阻害剤は遺伝子発現のエピジェネティックな制御機構に介入することにより、白内障を予防または治療している。したがって、ＨＡＴ阻害剤としての機能を有する物質を有効成分として含む白内障の予防剤または治療剤は、全て本発明の範囲に含まれる。 Thus, HAT inhibitors prevent or treat cataracts by intervening in epigenetic control mechanisms of gene expression. Therefore, all the preventive or therapeutic agents for cataracts containing a substance having a function as a HAT inhibitor as an active ingredient are included in the scope of the present invention.
　なお、上述した３種類の作用機序モデルは、〔実施例４〕において裏付けられている。 In addition, the above-mentioned three types of action mechanism models are supported in [Example 4].
　また、本発明の一態様は、ＨＡＴ阻害剤を有効成分とする白内障の予防薬または治療薬を用いる、白内障の予防方法または治療方法である。 One embodiment of the present invention is a method for preventing or treating cataract using a prophylactic or therapeutic agent for cataract containing an HAT inhibitor as an active ingredient.
　〔実施例１〕
　ガラクトース添加培地を用いた糖尿病白内障モデルを利用して、以下のＨＡＴ阻害剤における白内障の予防効果を調査した。 [Example 1]
Using a diabetic cataract model using a galactose-added medium, the following cataract preventive effects of HAT inhibitors were investigated.
　［実施例１－１］
　６週齢のＳＤラット（三協ラボサービス社製）の左右の眼球から、水晶体を摘出した。右眼から摘出した水晶体は、Ｍ１９９培地（SIGMA社製）に３０ｍＭのガラクトースを添加した培地にて培養し、糖尿病白内障を発症させたモデルとした。一方、左眼から摘出した水晶体は、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭの２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサン（abcam社製）を添加した培地にて培養した。培養にはインキュベーターを使用し、温度は３７℃に保った。なお、２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサンは、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とするＨＡＴ阻害剤である。 [Example 1-1]
The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from the right eye was cultured in a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA), and used as a model for developing diabetic cataract. On the other hand, the lens extracted from the left eye was obtained by adding 30 mM galactose and 40 μM 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane (abcam) to the M199 medium. Incubated in An incubator was used for the culture, and the temperature was maintained at 37 ° C. 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is a HAT inhibitor that targets HAT of the P300 / CBP family.
　培養開始から４日後、上記水晶体をそれぞれ培地から取り出し、ＳＺＸ１２（Olympas社製）により２０倍に拡大した顕微鏡写真を撮影した。上記顕微鏡写真を、図２の（ａ）に示す。 Four days after the start of culture, each of the above lenses was taken out of the medium, and a photomicrograph magnified 20 times with SZX12 (Olympas) was taken. The micrograph is shown in FIG.
　図２の（ａ）に示されているように、上記２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサンを添加した培地にて培養した水晶体は、上記２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサンを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 2 (a), the lens cultured in the medium supplemented with 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane is The turbidity of the cortex was kept low compared to the lens cultured in a medium not added with -bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane.
　［実施例１－２］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび１００μＭのＣＴＫ７Ａ（EMD Millipore社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＣＴＫ７Ａは、Ｐ３００およびＰＣＡＦを標的とするＨＡＴ阻害剤である。結果を図２の（ｂ）に示す。 [Example 1-2]
The lens was extracted from the left eye, and the experiment was carried out in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 μM CTK7A (EMD Millipore). It was. CTK7A is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
　図２の（ｂ）に示されているように、上記ＣＴＫ７Ａを添加した培地にて培養した水晶体は、上記ＣＴＫ７Ａを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 2 (b), the lens cultured in the medium supplemented with CTK7A suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CTK7A. It was done.
　［実施例１－３］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび２μＭのガルシノール（Selleckchem社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ガルシノールは、Ｐ３００およびＰＣＡＦを標的とするＨＡＴ阻害剤である。結果を図２の（ｃ）に示す。 [Example 1-3]
The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 2 μM garcinol (manufactured by Selleckchem) were added to the M199 medium. . Garcinol is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
　図２の（ｃ）に示されているように、上記ガルシノールを添加した培地にて培養した水晶体は、上記ガルシノールを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 2C, the lens cultured in the medium added with garcinol suppresses the turbidity of the cortex to be lower than the lens cultured in the medium not added with garcinol. It was done.
　［実施例１－４］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび２０μＭのアナカルド酸（abcam社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、アナカルド酸は、Ｐ３００およびＰＣＡＦを標的とするＨＡＴ阻害剤である。結果を図２の（ｄ）に示す。 [Example 1-4]
The lens was extracted from the left eye, and the experiment was carried out in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 20 μM anacardic acid (abcam). It was. Anacardic acid is a HAT inhibitor that targets P300 and PCAF. The results are shown in FIG.
　図２の（ｄ）に示されているように、上記アナカルド酸を添加した培地にて培養した水晶体は、上記アナカルド酸を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 2 (d), the lens cultured in the medium to which the anacardic acid was added was more turbid in the cortex than the lens cultured in the medium to which the anacardic acid was not added. It was kept low.
　［実施例１－５］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび５０μＭのＭＧ１４９（Selleckchem社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＭＧ１４９は、ＴＩＰ６０およびＭＯＺを標的とするＨＡＴ阻害剤である。結果を図２の（ｅ）に示す。 [Example 1-5]
The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 50 μM MG149 (manufactured by Selleckchem) were added to the M199 medium. . MG149 is a HAT inhibitor that targets TIP60 and MOZ. The results are shown in FIG.
　図２の（ｅ）に示されているように、上記ＭＧ１４９を添加した培地にて培養した水晶体は、上記ＭＧ１４９を添加しない培地にて培養した水晶体と比較して、皮質部の混濁がやや低く抑えられていた。 As shown in FIG. 2 (e), the lens cultured in the medium supplemented with MG149 has a slightly lower turbidity in the cortex than the lens cultured in the medium not added with MG149. It was suppressed.
　［実施例１－６］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭのＣ６４６（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、Ｃ６４６は、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とするＨＡＴ阻害剤である。結果を図３の（ａ）に示す。 [Example 1-6]
The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 40 μM C646 (manufactured by SIGMA) were added to the M199 medium. . C646 is a HAT inhibitor that targets P300 / CBP family HAT. The results are shown in FIG.
　図３の（ａ）に示されているように、上記Ｃ６４６を添加した培地にて培養した水晶体は、上記Ｃ６４６を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 3A, the lens cultured in the medium supplemented with C646 has a lower turbidity in the cortex than the lens cultured in the medium not supplemented with C646. It was done.
　［実施例１－７］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭのＣＰＴＨ２（Cayman社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＣＰＴＨ２は、ＧＣＮ５を標的とするＨＡＴ阻害剤である。結果を図３の（ｂ）に示す。 [Example 1-7]
The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 μM CPTH2 (manufactured by Cayman) to the M199 medium. . CPTH2 is a HAT inhibitor that targets GCN5. The results are shown in FIG.
　図３の（ｂ）に示されているように、上記ＣＰＴＨ２を添加した培地にて培養した水晶体は、上記ＣＰＴＨ２を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 3 (b), the lens cultured in the medium added with CPTH2 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CPTH2. It was done.
　［実施例１－８］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび５００μＭのブチロラクトン３（abcam社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ブチロラクトン３は、ＧＣＮ５を標的とするＨＡＴ阻害剤である。結果を図３の（ｃ）に示す。 [Example 1-8]
The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 500 μM butyrolactone 3 (abcam) to the M199 medium. It was. Butyrolactone 3 is a HAT inhibitor that targets GCN5. The results are shown in FIG.
　図３の（ｃ）に示されているように、上記ブチロラクトン３を添加した培地にて培養した水晶体は、上記ブチロラクトン３を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 3 (c), the lens cultured in the medium added with butyrolactone 3 has more turbidity in the cortex than the lens cultured in the medium not added with butyrolactone 3. It was kept low.
　［実施例１－９］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび１００μＭの没食子酸（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、没食子酸は、非特異的なＨＡＴ阻害剤である。結果を図３の（ｄ）に示す。 [Example 1-9]
The lens extracted from the left eye was subjected to the same procedure as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 μM gallic acid (manufactured by SIGMA). It was. In addition, gallic acid is a non-specific HAT inhibitor. The results are shown in FIG.
　図３の（ｄ）に示されているように、上記没食子酸を添加した培地にて培養した水晶体は、上記没食子酸を添加しない培地にて培養した水晶体と比較して、皮質部の混濁がやや低く抑えられていた。 As shown in FIG. 3 (d), the lens cultured in the medium added with gallic acid is more turbid in the cortex than the lens cultured in the medium not added with gallic acid. It was a little lower.
　［実施例１－１０］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび５０μＭの（－）－エピガロカテキンガラート（和光純薬工業社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、（－）－エピガロカテキンガラートは、非特異的なＨＡＴ阻害剤である。結果を図３の（ｅ）に示す。 [Example 1-10]
Example 1 except that the lens removed from the left eye was cultured in the above M199 medium supplemented with 30 mM galactose and 50 μM (−)-epigallocatechin gallate (Wako Pure Chemical Industries, Ltd.). Experiments were performed in the same procedure as for -1. Note that (−)-epigallocatechin gallate is a non-specific HAT inhibitor. The results are shown in FIG.
　図３の（ｅ）に示されているように、上記（－）－エピガロカテキンガラートを添加した培地にて培養した水晶体は、上記（－）－エピガロカテキンガラートを添加しない培地にて培養した水晶体と比較して、皮質部の混濁がやや低く抑えられていた。 As shown in FIG. 3 (e), the lens cultured in the medium supplemented with the (−)-epigallocatechin gallate was added to the medium without the addition of the (−)-epigallocatechin gallate. Compared with the cultured lens, the turbidity of the cortex was somewhat lower.
　［実施例１－１１］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび２０μＭのＩＳＯＸ　ＤＵＡＬ（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＩＳＯＸ　ＤＵＡＬは、ＣＢＰおよびＢＲＤ４のブロモドメインを標的とするＨＡＴ阻害剤である。結果を図４の（ａ）に示す。 [Example 1-11]
The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 20 μM ISOX DUAL (manufactured by SIGMA) were added to the M199 medium. It was. ISOX DUAL is a HAT inhibitor that targets the bromodomain of CBP and BRD4. The results are shown in FIG.
　図４の（ａ）に示されているように、上記ＩＳＯＸ　ＤＵＡＬを添加した培地にて培養した水晶体は、上記ＩＳＯＸ　ＤＵＡＬを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 4 (a), the lens cultured in the medium supplemented with the above ISOX DUAL is more turbid in the cortex than the lens cultured in the medium not added with the above ISOX DUAL. It was kept low.
　［実施例１－１２］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび２μＭのプルンバギン（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、プルンバギンは、Ｐ３００を標的とするＨＡＴ阻害剤である。結果を図４の（ｂ）に示す。 [Example 1-12]
The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 2 μM plumbagin (manufactured by SIGMA) were added to the M199 medium. . Plumbagin is a HAT inhibitor that targets P300. The results are shown in FIG.
　図４の（ｂ）に示されているように、上記プルンバギンを添加した培地にて培養した水晶体は、上記プルンバギンを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 4 (b), the lens cultured in the medium to which the plumbagin was added had less turbidity in the cortex compared to the lens cultured in the medium to which the plumbagin was not added. It was done.
　［実施例１－１３］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび１００μＭのＴＨ１８３４（axon medchem社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＴＨ１８３４は、ＴＩＰ６０を標的とするＨＡＴ阻害剤である。結果を図４の（ｃ）に示す。 [Example 1-13]
The lens was extracted from the left eye, and the experiment was performed in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 100 μM TH1834 (manufactured by axon medchem). It was. TH1834 is a HAT inhibitor that targets TIP60. The results are shown in FIG.
　図４の（ｃ）に示されているように、上記ＴＨ１８３４を添加した培地にて培養した水晶体は、上記ＴＨ１８３４を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 4 (c), the lens cultured in the medium added with TH1834 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with TH1834. It was done.
　［実施例１－１４］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび１００μＭのＳＰＶ１０６（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＳＰＶ１０６は、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とするＨＡＴ阻害剤である。結果を図４の（ｄ）に示す。 [Example 1-14]
The experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 100 μM SPV106 (manufactured by SIGMA) were added to the M199 medium. . SPV106 is a HAT inhibitor that targets the P300 / CBP family HAT. The results are shown in FIG.
　図４の（ｄ）に示されているように、上記ＳＰＶ１０６を添加した培地にて培養した水晶体は、上記ＳＰＶ１０６を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 4 (d), the lens cultured in the medium to which the SPV 106 is added suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium to which the SPV 106 is not added. It was done.
　［実施例１－１５］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭのＷｉｎｄｏｒｐｈｅｎ（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、Ｗｉｎｄｏｒｐｈｅｎは、非特異的なＨＡＴ阻害剤である。結果を図４の（ｅ）に示す。 [Example 1-15]
An experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 μM Windorphen (manufactured by SIGMA) to the M199 medium. . Windorphen is a non-specific HAT inhibitor. The results are shown in FIG.
　図４の（ｅ）に示されているように、上記Ｗｉｎｄｏｒｐｈｅｎを添加した培地にて培養した水晶体は、上記Ｗｉｎｄｏｒｐｈｅｎを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 4 (e), the lens cultured in the medium added with Windorphen suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with Windorphen. It was done.
　［実施例１－１６］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭのＲｅｍｏｄｅｌｉｎ（Cayman社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、Ｒｅｍｏｄｅｌｉｎは、ＮＡＴ１０を標的とするＨＡＴ阻害剤である。結果を図５の（ａ）に示す。 [Example 1-16]
The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 μM Remodelin (manufactured by Cayman) to the M199 medium. . Remodelin is a HAT inhibitor that targets NAT10. The results are shown in FIG.
　図５の（ａ）に示されているように、上記Ｗｉｎｄｏｒｐｈｅｎを添加した培地にて培養した水晶体は、上記Ｗｉｎｄｏｒｐｈｅｎを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 5 (a), the lens cultured in the medium added with Windorphen suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with Windorphen. It was done.
　［実施例１－１７］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭのエンベリン（abcam社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、エンベリンは、ＰＣＡＦを標的とするＨＡＴ阻害剤である。結果を図５の（ｂ）に示す。 [Example 1-17]
The experiment was performed in the same manner as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 40 μM Embelin (abcam) to the M199 medium. . Embelin is a HAT inhibitor that targets PCAF. The results are shown in FIG.
　図５の（ｂ）に示されているように、上記エンベリンを添加した培地にて培養した水晶体は、上記エンベリンを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 5 (b), the lens cultured in the medium supplemented with the above-described embellin suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with the above-described embellin. It was done.
　［実施例１－１８］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび２００μＭのＥＭＬ４２５（axon medchem社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＥＭＬ４２５は、Ｐ３００／ＣＢＰファミリーのＨＡＴを標的とするＨＡＴ阻害剤である。結果を図５の（ｃ）に示す。 [Example 1-18]
The lens extracted from the left eye was subjected to the same procedure as in Example 1-1 except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 200 μM EML425 (manufactured by axon medchem). It was. EML425 is a HAT inhibitor that targets P300 / CBP family HAT. The results are shown in FIG.
　図５の（ｃ）に示されているように、上記ＥＭＬ４２５を添加した培地にて培養した水晶体は、上記ＥＭＬ４２５を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 5 (c), the lens cultured in the medium to which the EML425 is added suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium to which the EML425 is not added. It was done.
　［実施例１－１９］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび５μＭのＣＢＰ３０（Cayman社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＣＢＰ３０は、Ｐ３００／ＣＢＰファミリーのＨＡＴのブロモドメインを標的とするＨＡＴ阻害剤である。結果を図５の（ｄ）に示す。 [Example 1-19]
An experiment was performed in the same manner as in Example 1-1 except that the lens extracted from the left eye was cultured in a medium obtained by adding 30 mM galactose and 5 μM CBP30 (manufactured by Cayman) to the M199 medium. . CBP30 is a HAT inhibitor that targets the bromodomain of the P300 / CBP family HAT. The results are shown in FIG.
　図５の（ｄ）に示されているように、上記ＣＢＰ３０を添加した培地にて培養した水晶体は、上記ＣＢＰ３０を添加しない培地にて培養した水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 5 (d), the lens cultured in the medium added with CBP30 suppresses the turbidity of the cortex to be lower than that of the lens cultured in the medium not added with CBP30. It was done.
　［参考例１－１］
　左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび０．８μＭのＴＳＡ（和光純薬工業社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により実験を行った。なお、ＴＳＡは、ヒストン脱アセチル化酵素（ＨＤＡＣ）阻害剤である。結果を図５の（ｅ）に示す。 [Reference Example 1-1]
The same procedure as in Example 1-1, except that the lens extracted from the left eye was cultured in a medium in which 30 mM galactose and 0.8 μM TSA (manufactured by Wako Pure Chemical Industries, Ltd.) were added to the M199 medium. The experiment was conducted. TSA is a histone deacetylase (HDAC) inhibitor. The results are shown in FIG.
　図５の（ｅ）に示されているように、上記ＴＳＡを添加した培地にて培養した水晶体は、上記ＴＳＡを添加しない培地にて培養した水晶体と比較して、皮質部の混濁が増加していた。 As shown in FIG. 5 (e), the lens cultured in the medium to which TSA was added increased the turbidity of the cortex compared with the lens cultured in the medium to which TSA was not added. It was.
　以上の実施例および参考例で観察された現象からは、ヒストンがアセチル化されている程度が白内障の発症に関係しており、ヒストンのアセチル化が阻害されると白内障が予防され、ヒストンの脱アセチル化が阻害されると白内障が促進されることが示唆される。 From the phenomena observed in the above Examples and Reference Examples, the degree to which histones are acetylated is related to the development of cataracts, and when histone acetylation is inhibited, cataracts are prevented and histone depletion occurs. It is suggested that cataract is promoted when acetylation is inhibited.
　〔実施例２〕
　培地に添加するＨＡＴ阻害剤（Ｃ６４６）またはＨＤＡＣ阻害剤（ＴＳＡ）の濃度を変化させ、水晶体に生じる混濁を定量化した。 [Example 2]
The concentration of the HAT inhibitor (C646) or HDAC inhibitor (TSA) added to the medium was changed, and the turbidity generated in the lens was quantified.
　まず、左眼から摘出した水晶体を、上記Ｍ１９９培地に、３０ｍＭのガラクトースおよび４０μＭのＣ６４６（SIGMA社製）を添加した培地にて培養した以外は、実施例１－１と同様の手順により、培養後の水晶体を写した顕微鏡写真を得た。次に、ａｄｏｂｅ　ｐｈｏｔｏｓｈｏｐ（登録商標）　ｃｓ６を利用して、上記顕微鏡写真をグレースケール画像に変換した。次に、左眼の水晶体（ＨＡＴ阻害剤添加培地にて培養）を写した上記グレースケール画像から、右眼の水晶体（ＨＡＴ阻害剤無添加培地にて培養）を写した上記グレースケール画像を減算し、輝度を測定した。当該測定によって求められた輝度を、「水晶体の混濁度」として、グラフに示した（図６）。 First, the lens extracted from the left eye was cultured in the same manner as in Example 1-1, except that the lens was cultured in the above M199 medium supplemented with 30 mM galactose and 40 μM C646 (manufactured by SIGMA). A photomicrograph of the later lens was obtained. Next, the above-mentioned micrograph was converted into a gray scale image using Adobe photoshop (registered trademark) cs6. Next, subtract the gray scale image of the right eye lens (cultured in a HAT inhibitor-free medium) from the gray scale image of the left eye lens (cultured in a HAT inhibitor-added medium). The brightness was measured. The luminance obtained by the measurement is shown in the graph as “turbidity of the crystalline lens” (FIG. 6).
　上記実験に加えて、添加するＨＡＴ阻害剤の濃度を、２０μＭ、１０μＭにそれぞれ変更し、同様の手順により水晶体の混濁度を測定した。結果を図６に示した。 In addition to the above experiment, the concentration of the HAT inhibitor to be added was changed to 20 μM and 10 μM, respectively, and the turbidity of the lens was measured by the same procedure. The results are shown in FIG.
　更に、ＨＡＴ阻害剤の代わりにＨＤＡＣ阻害剤を、それぞれ０．８μＭ、０．４μＭ、０．２μＭ添加した培地を用意し、同様の手順により水晶体の混濁度を測定した。結果を図６に示した。 Furthermore, media with 0.8 μM, 0.4 μM, and 0.2 μM added HDAC inhibitor instead of HAT inhibitor were prepared, and the turbidity of the lens was measured by the same procedure. The results are shown in FIG.
　本実験結果は、ＨＡＴ阻害剤が水晶体の混濁を抑制するのに対し、ＨＤＡＣ阻害剤は水晶体の混濁を促進することを示している。 This experimental result shows that the HAT inhibitor suppresses the opacity of the lens, whereas the HDAC inhibitor promotes the opacity of the lens.
　〔実施例３〕
　６週齢のＳＤラット（三協ラボサービス社製）の左右の眼球から、水晶体を摘出した。左右両眼から摘出した水晶体を、Ｍ１９９培地（SIGMA社製）に３０ｍＭのガラクトースを添加した培地にて２日間培養し、糖尿病白内障を発症させたモデルとした。その後、左眼の水晶体を３０ｍＭのガラクトースおよび４０μＭのＣ６４６を添加した培地に移した。一方、右眼の水晶体は培地を変更しなかった。培地変更から０日目（培養開始から２日目）、培地変更から２日目（培養開始から４日目）、培地変更から４日目（培養開始から６日目）に、上記水晶体をそれぞれ培地から取り出し、ＳＺＸ１２（Olympas社製）により２０倍に拡大した顕微鏡写真を撮影した。それぞれの写真を図７に示す。 Example 3
The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from both the left and right eyes was cultured in a medium in which 30 mM galactose was added to M199 medium (manufactured by SIGMA) for 2 days, and used as a model for developing diabetic cataract. Thereafter, the lens of the left eye was transferred to a medium supplemented with 30 mM galactose and 40 μM C646. On the other hand, the lens of the right eye did not change the medium. On the 0th day (2nd day from the start of culture) after the medium change, the 2nd day (4th day from the start of culture), and the 4th day (6th day from the start of culture) after the change of the medium, The sample was taken out of the medium, and a photomicrograph magnified 20 times with SZX12 (Olympas) was taken. Each photograph is shown in FIG.
　図７に示されているように、上記Ｃ６４６を添加した培地に移して培養した水晶体は、上記Ｃ６４６を添加しない培地にて培養し続けた水晶体と比較して、皮質部の混濁が低く抑えられていた。 As shown in FIG. 7, the lens transferred to the medium added with C646 and cultured has a lower turbidity of the cortex than the lens that has been cultured in the medium not added with C646. It was.
　以上の結果より、Ｃ６４６には、白内障の治療効果（進行を抑制する効果）があることが示された。 From the above results, it was shown that C646 has a therapeutic effect on cataract (an effect of suppressing progression).
　〔実施例４〕
　マイクロアレイを用いて遺伝子の発現を調査し、ＨＡＴ阻害剤が白内障を予防または治療するメカニズムを推定した。 Example 4
Microarrays were used to investigate gene expression and to estimate the mechanism by which HAT inhibitors prevent or treat cataracts.
　Ｍ１９９培地（SIGMA社製）、上記Ｍ１９９培地に３０ｍＭのガラクトースを添加した培地、上記Ｍ１９９培地に３０ｍＭのガラクトースおよび４０μＭのＨＡＴ阻害剤（Ｃ６４６）を添加した培地、並びに、上記Ｍ９９培地に３０ｍＭのガラクトースおよび０．８μＭのＨＤＡＣ阻害剤（ＴＳＡ）を添加した培地、を用意した。上述したそれぞれの培地にて、６週齢のＳＤラット（三協ラボサービス社製）の眼球から摘出した水晶体を培養した。培養にはインキュベーターを用い、培養温度は３７℃、培養期間は４日間であった。 M199 medium (manufactured by SIGMA), medium obtained by adding 30 mM galactose to M199 medium, medium obtained by adding 30 mM galactose and 40 μM HAT inhibitor (C646) to M199 medium, and 30 mM galactose to M99 medium And a medium supplemented with 0.8 μM HDAC inhibitor (TSA). In each medium described above, the lens extracted from the eyeball of a 6-week-old SD rat (Sankyo Lab Service Co., Ltd.) was cultured. An incubator was used for the culture, the culture temperature was 37 ° C., and the culture period was 4 days.
　４日後、上記水晶体をそれぞれの培地から取り出し、ＴＲＩＺＯＬ（登録商標）（LifeTechnologies社製）に含浸してからバイオマッシャー（登録商標）（和光純薬工業社製）よって破砕し、ＲＮＡを抽出した。なお、詳細なＲＮＡの抽出方法は、ＴＲＩＺＯＬ（登録商標）の取扱説明書に記載されている。以上の手順にて作製した試料を、マイクロアレイ分析用の試料とした。 Four days later, the above lens was taken out from each medium, impregnated with TRIZOL (registered trademark) (manufactured by Life Technologies), and then crushed by Biomasher (registered trademark) (manufactured by Wako Pure Chemical Industries) to extract RNA. Detailed RNA extraction methods are described in the TRIZOL (registered trademark) instruction manual. The sample prepared by the above procedure was used as a sample for microarray analysis.
　上記試料に、マイクロアレイ用チップ（Affymetrix社製）を用いて、それぞれの水晶体における遺伝子の発現を調査した。得られたデータはＥｘｃｅｌ（登録商標）を用いて分析した。分析結果から、ＨＡＴ阻害剤添加培地で培養した水晶体と、ＨＤＡＣ阻害剤添加培地で培養した水晶体との間で異なる発現量を示した遺伝子を選抜した。具体的には、ガラクトースのみを添加した培地で培養した水晶体における遺伝子の発現量を１とし、以下の条件（ｉ）または（ｉｉ）に該当する遺伝子を選抜した。
（ｉ）Ｍ１９９培地（コントロール）並びにガラクトースおよびＨＡＴ阻害剤を添加した培地における発現量が１．５以上、かつ、ガラクトースおよびＨＤＡＣ阻害剤を添加した培地における発現量が０．５以下。
（ｉｉ）Ｍ１９９培地（コントロール）並びにガラクトースおよびＨＡＴ阻害剤を添加した培地における発現量が０．５以下、かつ、ガラクトースおよびＨＤＡＣ阻害剤を添加した培地における発現量が１．５以上。 Using the microarray chip (manufactured by Affymetrix) as the sample, gene expression in each lens was examined. The obtained data was analyzed using Excel (registered trademark). From the analysis results, genes that showed different expression levels were selected between the lens cultured in the HAT inhibitor-added medium and the lens cultured in the HDAC inhibitor-added medium. Specifically, the expression level of a gene in a lens cultured in a medium containing only galactose was set to 1, and a gene corresponding to the following condition (i) or (ii) was selected.
(I) The expression level in the M199 medium (control) and the medium added with galactose and HAT inhibitor is 1.5 or more, and the expression level in the medium added with galactose and HDAC inhibitor is 0.5 or less.
(Ii) The expression level in the M199 medium (control) and the medium to which galactose and HAT inhibitors are added is 0.5 or less, and the expression level in the medium to which galactose and HDAC inhibitors are added is 1.5 or more.
　上記条件に該当した遺伝子および当該遺伝子の発現量を、表２に示す。 Table 2 shows the genes corresponding to the above conditions and the expression levels of the genes.
Figure JPOXMLDOC01-appb-T000029
 　表２に記載の遺伝子のうち、ＰＬＫ３の挙動から推定される、ＨＡＴ阻害剤による白内障の予防または治療効果の作用機序の一例が、図１の（ａ）である。ＡＬＤＨ１Ａ１の挙動から推定される、ＨＡＴ阻害剤による白内障の予防または治療効果の作用機序の一例が、図１の（ｂ）である。ＧＪＡ１（Ｃｘ４３）の挙動から推定される、ＨＡＴ阻害剤による白内障の予防または治療効果の作用機序の一例が、図１の（ｃ）である。
Figure JPOXMLDOC01-appb-T000029
 FIG. 1 (a) shows an example of the mechanism of action for preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of PLK3 among the genes listed in Table 2. FIG. 1B shows an example of the action mechanism of the effect of preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of ALDH1A1. FIG. 1 (c) shows an example of the action mechanism of the effect of preventing or treating cataract by a HAT inhibitor, which is estimated from the behavior of GJA1 (Cx43).
　〔実施例５〕
　ＨＡＴ阻害剤の組み合わせによる、白内障の治療効果について検討した。 Example 5
The therapeutic effect of cataract by the combination of HAT inhibitors was examined.
　［実施例５－１］
　Ｍ１９９培地（SIGMA社製）に、３０ｍＭのガラクトース、および最終濃度０．８％のＤＭＳＯを添加した培地を用意した。上記培地にて、６週齢のＳＤラット（三協ラボサービス社製）の左右両眼から摘出した水晶体を、３７℃、５％ＣＯ２条件下で４日間培養し、糖尿病白内障を発症させたモデルとした。 [Example 5-1]
A medium in which 30 mM galactose and DMSO having a final concentration of 0.8% were added to M199 medium (manufactured by SIGMA) was prepared. In the above medium, a lens extracted from both left and right eyes of a 6-week-old SD rat (Sankyo Lab Service Co., Ltd.) was cultured at 37 ° C. under 5% CO 2 for 4 days to develop diabetic cataract. Model.
　その後、左眼の水晶体を、（１）３０ｍＭのガラクトース、ならびに（２）１０μＭのＣＢＰ３０および８０μＭのＣＰＴＨ２（共に最終濃度０．８％のＤＭＳＯに溶解させたもの）を添加した培地に移した。一方、右眼の水晶体は、Ｍ１９９培地（SIGMA社製）に、３０ｍＭのガラクトース、および最終濃度０．８％のＤＭＳＯを添加した培地を再度調製し、当該培地に移した。培地変更から０日目（培養開始から４日目）、培地変更から２日目（培養開始から６日目）、培地変更から４日目（培養開始から８日目）に、上記水晶体をそれぞれ培地から取り出し、ＳＺＸ１２（Olympas社製）により１０倍に拡大した顕微鏡写真を撮影した。その結果を図８の（ａ）に示す。 Thereafter, the lens of the left eye was transferred to a medium supplemented with (1) 30 mM galactose, and (2) 10 μM CBP30 and 80 μM CPTH2 (both dissolved in DMSO having a final concentration of 0.8%). On the other hand, for the lens of the right eye, a medium in which 30 mM galactose and DMSO with a final concentration of 0.8% were added to M199 medium (manufactured by SIGMA) was prepared again and transferred to the medium. On the 0th day (4th day from the start of culture) after the medium change, the 2nd day (6th day from the start of culture), and the 4th day (8th day from the start of culture) after the change of the medium, The sample was taken out of the medium, and a photomicrograph was magnified 10 times with SZX12 (Olympas). The result is shown in FIG.
　上記水晶体を、ＦＧ（Formalin-Glutaraldehyde）液（Formalin:武藤化学製、Glutaraldehyde:和光純薬工業製）中に、４℃にて３日間浸漬した後、１０％ホルマリン液に浸漬した。染色した切片の作製は、新組織化学研究所に依頼した。 The lens was immersed in an FG (Formalin-Glutaraldehyde) solution (Formalin: manufactured by Muto Chemical Co., Ltd., Glutaraldehyde: manufactured by Wako Pure Chemical Industries, Ltd.) at 4 ° C. for 3 days, and then immersed in a 10% formalin solution. The new histochemical laboratory was commissioned to prepare stained sections.
　上記切片をＩＸ７０（Olympas社製）により１００倍に拡大した顕微鏡写真を撮影した。その結果を図８の（ｂ）に示す。同図において、左側は上記切片の全体像、右側は赤道部近傍の拡大像である。 A micrograph was taken in which the section was magnified 100 times with IX70 (Olympas). The result is shown in FIG. In the figure, the left side is the whole image of the above section, and the right side is an enlarged image near the equator.
　さらに、上述の培養条件を以下の条件に変更した実験を行った。
実験１－１：左眼の水晶体を、３０ｍＭのガラクトースおよび１０μＭのＣＢＰ３０（最終濃度０．８％のＤＭＳＯに溶解させたもの）を添加した培地にて培養した。
実験１－２：左眼の水晶体を、３０ｍＭのガラクトースおよび８０μＭのＣＰＴＨ２（最終濃度０．８％のＤＭＳＯに溶解させたもの）を添加した培地にて培養した。 Furthermore, the experiment which changed the above-mentioned culture conditions into the following conditions was conducted.
Experiment 1-1: The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 10 μM CBP30 (dissolved in DMSO at a final concentration of 0.8%).
Experiment 1-2: The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 80 μM CPTH2 (dissolved in DMSO at a final concentration of 0.8%).
　それぞれの実験において、培地変更から０日目（培養開始から４日目）、培地変更から２日目（培養開始から６日目）、培地変更から４日目（培養開始から８日目）に、上記水晶体をそれぞれ培地から取り出し、ＳＺＸ１２（Olympas社製）により１０倍に拡大した顕微鏡写真を撮影した。実験１－１の結果を図９の（ａ）に、実験１－２の結果を図９の（ｂ）に、それぞれ示す。 In each experiment, on the 0th day (4th day from the start of culture) after the medium change, on the 2nd day (6th day from the start of culture), and on the 4th day (8th day from the start of culture) after the medium change Each of the above lenses was taken out of the medium, and a photomicrograph magnified 10 times with SZX12 (Olympas) was taken. The result of Experiment 1-1 is shown in FIG. 9 (a), and the result of Experiment 1-2 is shown in FIG. 9 (b).
　（結果）
　図８の（ａ）に示されているように、ＣＢＰ３０およびＣＰＴＨ２の組み合わせを添加した培地に移して培養した水晶体は、ＣＢＰ３０およびＣＰＴＨ２の組み合わせを添加しない培地にて培養し続けた水晶体と比較して、皮質部の混濁が低く抑えられていた。このことは、図８の（ｂ）において、ＣＢＰ３０およびＣＰＴＨ２の組み合わせを添加した培地に移して培養した水晶体では、皮質部の崩壊が観察されないことからも判る。 (result)
As shown in FIG. 8 (a), the lens transferred and cultured in the medium to which the combination of CBP30 and CPTH2 was added was compared with the lens that had been cultured in the medium to which the combination of CBP30 and CPTH2 was not added. Thus, the turbidity of the cortex was kept low. This can also be seen from the fact that in FIG. 8 (b), no cortical collapse was observed in the lens cultured after transferring to a medium supplemented with the combination of CBP30 and CPTH2.
　また、図８の（ａ）と、図９の（ａ）および（ｂ）とを比較すると、ＣＢＰ３０およびＣＰＴＨ２の組み合わせを添加した培地に移して培養した水晶体は、ＣＢＰ３０またはＣＰＴＨ２の一方のみを添加した培地に移して培養した水晶体よりも、皮質部の混濁が低く抑えられていた。 Further, comparing (a) of FIG. 8 with (a) and (b) of FIG. 9, the lens transferred and cultured in the medium to which the combination of CBP30 and CPTH2 was added had only one of CBP30 or CPTH2 added. The turbidity of the cortex was suppressed to be lower than that of the lens that had been transferred to the cultured medium and cultured.
　以上の結果より、ＣＢＰ３０およびＣＰＴＨ２の組み合わせには、白内障の治療効果（進行を抑制する効果）があることが示された。さらに、上記治療効果は、ＣＢＰ３０またはＣＰＴＨ２のみによる白内障の治療効果よりも、顕著に優れたものであった。 From the above results, it was shown that the combination of CBP30 and CPTH2 has a therapeutic effect on cataract (an effect of suppressing progression). Furthermore, the therapeutic effect was significantly superior to the therapeutic effect of cataracts using only CBP30 or CPTH2.
　［実施例５－２］
　実施例５－１において、左眼の水晶体を移す培地を、（１）３０ｍＭのガラクトース、ならびに（２）４０μＭのＣ６４６および８０μＭのＣＰＴＨ２（共に最終濃度０．８％のＤＭＳＯに溶解させたもの）を添加した培地に変更した以外は、同様の手順によって水晶体を培養した。その結果を図１０に示す。 [Example 5-2]
In Example 5-1, the medium for transferring the lens of the left eye was (1) 30 mM galactose, and (2) 40 μM C646 and 80 μM CPTH2 (both dissolved in DMSO at a final concentration of 0.8%) The lens was cultured by the same procedure except that the medium was changed to a medium supplemented with. The result is shown in FIG.
　また、上述の培養条件を以下の条件に変更した実験を行った。実験２－１の結果を図１１の（ａ）に、実験２－２の結果を図１１の（ｂ）に、それぞれ示す。
実験２－１：左眼の水晶体を、３０ｍＭのガラクトースおよび４０μＭのＣ６４６（最終濃度０．８％のＤＭＳＯに溶解させたもの）を添加した培地にて培養した。
実験２－２：左眼の水晶体を、３０ｍＭのガラクトースおよび８０μＭのＣＰＴＨ２（最終濃度０．８％のＤＭＳＯに溶解させたもの）を添加した培地にて培養した。 Moreover, the experiment which changed the above-mentioned culture conditions into the following conditions was conducted. The results of Experiment 2-1 are shown in FIG. 11A, and the results of Experiment 2-2 are shown in FIG. 11B.
Experiment 2-1: The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 40 μM C646 (dissolved in DMSO at a final concentration of 0.8%).
Experiment 2-2: The lens of the left eye was cultured in a medium supplemented with 30 mM galactose and 80 μM CPTH2 (dissolved in DMSO at a final concentration of 0.8%).
　（結果）
　図１０に示されているように、Ｃ６４６およびＣＰＴＨ２の組み合わせを添加した培地に移して培養した水晶体は、Ｃ６４６およびＣＰＴＨ２の組み合わせを添加しない培地にて培養し続けた水晶体と比較して、皮質部の混濁が低く抑えられていた。 (result)
As shown in FIG. 10, the lens transferred to the medium supplemented with the combination of C646 and CPTH2 was cultured in the cortex compared with the lens that had been cultured in the medium without the combination of C646 and CPTH2. The turbidity of was kept low.
　また、　図１０と、図１１の（ａ）および（ｂ）とを比較すると、Ｃ６４６およびＣＰＴＨ２の組み合わせを添加した培地に移して培養した水晶体は、Ｃ６４６またはＣＰＴＨ２の一方のみを添加した培地に移して培養した水晶体よりも、皮質部の混濁が低く抑えられていた。 Further, comparing FIG. 10 with (a) and (b) of FIG. 11, the lens transferred to the medium added with the combination of C646 and CPTH2 was transferred to the medium added with only one of C646 or CPTH2. The turbidity of the cortex was lower than that of the cultured lens.
　以上の結果より、Ｃ６４６およびＣＰＴＨ２の組み合わせには、白内障の治療効果（進行を抑制する効果）があることが示された。さらに、上記治療効果は、Ｃ６４６またはＣＰＴＨ２のみによる白内障の治療効果よりも、顕著に優れたものであった。 From the above results, it was shown that the combination of C646 and CPTH2 has a therapeutic effect on cataract (an effect to suppress progression). Furthermore, the above therapeutic effect was remarkably superior to the therapeutic effect of cataract only by C646 or CPTH2.
　〔実施例６〕
　in vivo条件において、ＨＡＴ阻害剤による白内障の予防効果を検討した。 Example 6
Under in vivo conditions, the effect of HAT inhibitors to prevent cataracts was examined.
　３週齢のＳＤラット（三協ラボサービス社製）を、ガラクトース２５％を含有させた餌を摂餌させながら３日間飼育して、白内障を発症させた。４日目の摂餌前に、上記ＳＤラットの、左眼の前房内には５ｍＭのＣ６４６（１００％のＤＭＳＯに溶解させたもの）を、右眼の前房内には１００％のＤＭＳＯを、それぞれ５μＬずつ注入した。注入には、マイクロシリンダー（伊藤製作所製、イトー　マイクロシリンジ MS-NE05）に３３Ｇの注射針（テルモ製）を組み合わせた器具を用いた。以上の実験手法の概要を、図１２の（ａ）に示す。 Three-week-old SD rats (Sankyo Lab Service Co., Ltd.) were raised for 3 days while feeding with a diet containing 25% galactose to develop cataract. Before feeding on day 4, the SD rats had 5 mM C646 (dissolved in 100% DMSO) in the left anterior chamber and 100% DMSO in the right eye anterior chamber. 5 μL each was injected. For the injection, a device in which a 33 C injection needle (manufactured by Terumo) was combined with a micro cylinder (manufactured by Ito Seisakusho, Ito Microsyringe MS-NE05) was used. An outline of the above experimental method is shown in FIG.
　注入から３日後、左右両眼から水晶体を摘出し、ＳＺＸ１２（Olympas社製）により１０に拡大した顕微鏡写真を撮影した。その結果を図１２の（ｂ）に示す。なお、前房内への注入を行ったのは１回のみであった。また、注入後も、ガラクトース２５％を含有させた餌を摂餌させ続けた。 3 days after injection, the lens was extracted from both the left and right eyes, and a micrograph magnified to 10 with SZX12 (Olympas) was taken. The result is shown in FIG. The injection into the anterior chamber was performed only once. In addition, after the injection, food containing 25% galactose was continuously fed.
　（結果）
　図１２の（ｂ）に示されているように、Ｃ６４６の注入により、in vivo条件においても皮質部の混濁が低く抑えられていた。このことは、ＨＡＴ阻害剤の白内障の予防効果（進行を抑制する効果）を、より強く示唆している。 (result)
As shown in FIG. 12 (b), the turbidity of the cortex was suppressed to a low level even under in vivo conditions by injecting C646. This strongly suggests the cataract preventive effect (effect of suppressing progression) of the HAT inhibitor.
　本発明は、白内障の予防剤または治療剤に利用することができる。 The present invention can be used as an agent for preventing or treating cataract.

Claims (7)

  1. 　ＨＡＴ阻害剤を有効成分として含有している、白内障の予防剤または治療剤。 A preventive or therapeutic agent for cataract that contains a HAT inhibitor as an active ingredient.
  2. 　上記ＨＡＴ阻害剤は、ＨＡＴ１、ＮＡＡ６０、ＧＣＮ５、ＰＣＡＦ、ＴＩＰ６０、ＭＯＺ、ＭＯＲＦ、ＨＢＯ１、ＭＯＦ、Ｐ３００、ＣＢＰ、ＴＡＦ１、ＴＩＦＩＩＩＣ９０、ＳＲＣ１、ＳＣＲ３、Ｐ６００、ＣＬＯＣＫおよびＮＡＴ１０からなる群より選択される１種以上の物質を標的とするものである、請求項１に記載の白内障の予防剤または治療剤。 The HAT inhibitor is one selected from the group consisting of HAT1, NAA60, GCN5, PCAF, TIP60, MOZ, MORF, HBO1, MOF, P300, CBP, TAF1, TIFIIIC90, SRC1, SCR3, P600, CLOCK and NAT10. The preventive or therapeutic agent for cataract according to claim 1, which targets the above substances.
  3. 　上記ＨＡＴ阻害剤は、ポリフェノール由来の化合物、構造中にヘテロ環を含んでいる化合物、安息香酸誘導体、またはα－β不飽和カルボニル化合物である、請求項１または２に記載の白内障の予防剤または治療剤。 3. The prophylactic agent for cataract according to claim 1 or 2, wherein the HAT inhibitor is a compound derived from polyphenol, a compound containing a heterocycle in the structure, a benzoic acid derivative, or an α-β unsaturated carbonyl compound. Therapeutic agent.
  4. 　上記ＨＡＴ阻害剤は、クルクミン、２，６－ビス（（ｅ）－３－ブロモ－４－ヒドロキシベンジリデン）シクロヘキサン、ＣＴＫ７Ａ、Ｅｐｉｇｅｎｅｔｉｃ　Ｍｕｌｔｉｐｌｅ　Ｌｉｇａｎｄ、ガルシノール、アナカルド酸、ＭＧ１４９、Ｃ６４６、ＮＵ９０５６、ＣＰＴＨ２、５－クロロ－２－（４－ニトロフェニル）－３（２Ｈ）－イソチアゾロン、ブチロラクトン３、没食子酸、（－）－エピガロカテキンガラート、ＥＭＬ４２５、Ｌ００２、ＩＳＯＸ　ＤＵＡＬ、プルンバギン、ＴＨ１８３４、ＳＰＶ１０６、Ｗｉｎｄｏｒｐｈｅｎ、ケトミン、Ｒｅｍｏｄｅｌｉｎ、エンベリン、Ｉｓｃｈｅｍｉｎ、ＣＢＰ３０およびＫＧ５０１からなる群より選択される１種以上の物質、または当該物質の誘導体もしくは塩である、請求項１または２に記載の白内障の予防剤または治療剤。 The HAT inhibitors include curcumin, 2,6-bis ((e) -3-bromo-4-hydroxybenzylidene) cyclohexane, CTK7A, Epigenetic Multiple Ligand, garcinol, anacardic acid, MG149, C646, NU9056, CPTH2, 5- Chloro-2- (4-nitrophenyl) -3 (2H) -isothiazolone, butyrolactone 3, gallic acid, (−)-epigallocatechin gallate, EML425, L002, ISOX DUAL, plumbagin, TH1834, SPV106, Windorphen, ketomin 2. One or more substances selected from the group consisting of Remodelin, Embelin, Ischemin, CBP30 and KG501, or a derivative or salt of the substance. Prophylactic or therapeutic agents of cataracts according to the other two.
  5. 　投与剤型が点眼剤である、請求項１～４の何れか１項に記載の白内障の予防剤または治療剤。 The preventive or therapeutic agent for cataract according to any one of claims 1 to 4, wherein the dosage form is eye drops.
  6. 　上記白内障は、糖尿病白内障である、請求項１～５の何れか１項に記載の白内障の予防剤または治療剤。 The preventive or therapeutic agent for cataract according to any one of claims 1 to 5, wherein the cataract is diabetic cataract.
  7. 　白内障の予防剤または治療剤を製造するための、ＨＡＴ阻害剤の使用。 使用 Use of a HAT inhibitor to produce a preventive or therapeutic agent for cataracts.
PCT/JP2017/019034 2016-10-24 2017-05-22 Preventive agent and therapeutic agent for cataracts, and use of hat inhibitor for production thereof WO2018078922A1 (en)

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