JP7033317B2 - 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 - Google Patents
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 Download PDFInfo
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- JP7033317B2 JP7033317B2 JP2018547203A JP2018547203A JP7033317B2 JP 7033317 B2 JP7033317 B2 JP 7033317B2 JP 2018547203 A JP2018547203 A JP 2018547203A JP 2018547203 A JP2018547203 A JP 2018547203A JP 7033317 B2 JP7033317 B2 JP 7033317B2
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- cataract
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- inhibitor
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
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Description
[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、冠状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。
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。
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。
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。
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。
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。
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。
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。
[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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
M199培地(SIGMA社製)に、30mMのガラクトース、およびDMSO(最終濃度が0.8%になるように調製したもの)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。
実験1-1:左眼の水晶体を、30mMのガラクトースおよびCBP30(最終濃度が10μMになるように調製したもの)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CPTH2(最終濃度が80μMになるように調製したもの)を添加した培地にて培養した。
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。
M199培地(SIGMA社製)に、30mMのガラクトース、およびDMSO(最終濃度が0.8%になるように調製したもの)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3日間培養し、糖尿病白内障を発症させたモデルとした。
実験2-1:左眼の水晶体を、30mMのガラクトースおよびC646(最終濃度が40μMになるように調製したもの)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CPTH2(最終濃度が80μMになるように調整したもの)を添加した培地にて培養した。
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。
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。
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。
M199培地(SIGMA社製)に、30mMのガラクトース、およびDMSO(最終濃度が0.8%になるように調製したもの)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3日間培養し、糖尿病白内障を発症させたモデルとした。
図13に示されているように、TH1834を添加した培地に移して培養した水晶体は、TH1834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。このことから、TH1834は、一剤のみで白内障の治療効果を有していることが示唆される。
Claims (5)
- HAT阻害剤を有効成分として含有している、白内障の治療剤であって、
上記HAT阻害剤は、下記(a)~(d)からなる群より選択される1種類以上である、治療剤。
(a)TH1834
(b)CBP30およびCPTH2の組合せ
(c)C646およびCPTH2の組合せ
(d)上記(a)~(c)の誘導体または塩 - 投与剤型が点眼剤である、請求項1に記載の白内障の治療剤。
- 上記白内障は、糖尿病白内障である、請求項1または2に記載の白内障の治療剤。
- 白内障の治療剤を製造するための、HAT阻害剤の使用であって、
上記HAT阻害剤は、下記(a)~(d)からなる群より選択される1種類以上である、使用。
(a)TH1834
(b)CBP30およびCPTH2の組合せ
(c)C646およびCPTH2の組合せ
(d)上記(a)~(c)の誘導体または塩 - 上記白内障は、糖尿病白内障である、請求項4に記載の使用。
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