JP2020514411A - チオールイソメラーゼ阻害剤およびその使用 - Google Patents
チオールイソメラーゼ阻害剤およびその使用 Download PDFInfo
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- JP2020514411A JP2020514411A JP2019562217A JP2019562217A JP2020514411A JP 2020514411 A JP2020514411 A JP 2020514411A JP 2019562217 A JP2019562217 A JP 2019562217A JP 2019562217 A JP2019562217 A JP 2019562217A JP 2020514411 A JP2020514411 A JP 2020514411A
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- cancer
- zafirlukast
- extracellular
- thiol isomerase
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Abstract
Description
本明細書において使用される場合、「細胞外チオールイソメラーゼ」としては、少なくともプロテインジスルフィドイソメラーゼ(PDI)、チオレドキシン(TRX)、ならびに以下の小胞体内在性タンパク質:ERp5、ERp57、およびERp72が挙げられる。
本明細書において使用される場合、「細胞外チオールイソメラーゼ阻害剤化合物」は、1つまたは複数の細胞外チオールイソメラーゼの阻害剤である。例示的な細胞外チオールイソメラーゼ阻害剤化合物としては、ザフィルルカスト、モンテルカスト、CGP−13501(CAS登録番号56189−68−5)、CGP−7930(CAS登録番号57717−80−3)、アロセトロン、バルサラジド、ベンセラジド、ブタクラモール、レバドパ、メサラジン、オクスカルバゼピン、これらの薬学的に許容される塩、プロドラッグ、および/または固体状態形態が挙げられる。1つまたは複数の細胞外チオールイソメラーゼの阻害剤として、これらの化合物の1つまたは複数を抗血栓剤、および抗凝固剤、抗炎症剤、抗ウイルス剤、化学療法剤または抗がん剤など、またはこれらの組合せとして使用することができる。
1つまたは複数の細胞外チオールイソメラーゼの阻害は、血小板凝集、顆粒分泌、付着、血栓形成およびフィブリン生成を遮断するので、細胞外チオールイソメラーゼは、うっ血および血栓症の調節に関与する。抗血栓剤は、危険な血餅(急性血栓症)の予防(一次予防、二次予防)または治療のために治療的に使用され得る。
PDI阻害はがん療法のための実行可能な標的である。Xuら、「Protein disulfide isomerase:a promising target for cancer therapy」、Drug Discovery Today、第19巻、第3号、2014年3月を参照。
チオールイソメラーゼ、特にPDIはまた、HIV−1の侵入に関与する。広範なチオールイソメラーゼ阻害剤(例えば、ザフィルルカスト)の使用は、Khanら、「Discovery of a Small Molecule PDI Inhibitor That Inhibits Reduction of HIV−1 Envelope Glycoprotein gpl20.」、ACS Chemical Biology、第6巻、第3号、2011年3月により実証されるように、保護効果を付与してウイルスの侵入を防止し得る。
細胞外チオールイソメラーゼ阻害剤化合物を用いて治療される炎症は、肺、関節、結合組織、目、鼻、腸、腎臓、肝臓、皮膚、中枢神経系、血管系または心臓の炎症であり得る。PDIは、血管炎症および組織損傷の間の好中球の誘引および自然免疫応答の活性化において不可欠な役割を果たすことが実証されている。
チオールイソメラーゼは脳に存在し、クロイツフェルト・ヤコブ病、アルツハイマー病、ハンチントン病、およびパーキンソン病などの神経学的フォールディング障害を有する患者において上方調節される。広範なチオールイソメラーゼ阻害剤(例えば、ザフィルルカスト)の使用は、神経変性疾患におけるPDIサブファミリーメンバーと関連付けられる増加した活性酸素種損傷およびアポトーシスに起因する、神経学的変性を予防しまたは低減させるため、神経変性障害を治療するため、ならびに神経学的疾患および障害を治療するために、保護効果を付与し得る。先行する研究は、PDI阻害剤がミスフォールディングしたハンチントンおよびb−アミロイドタンパク質と関連付けられる毒性を抑制できることを実証した。
1つまたは複数の細胞外チオールイソメラーゼ阻害剤化合物は、純粋な化学物質として投与することができ、または医薬組成物として投与することができる。したがって、実施形態は、薬学的に許容される担体と共に細胞外チオールイソメラーゼ阻害剤化合物またはその薬学的に許容される塩を含む医薬組成物を提供する。医薬組成物は、唯一の活性剤として細胞外チオールイソメラーゼ阻害剤化合物もしくはその薬学的に許容される塩を含有してもよく、または1つもしくは複数の追加の活性剤を含有してもよい。
組換えチオールイソメラーゼはAbCam(Cambridge MA)から購入し、組換えインスリン(ウシ)、バシトラシン、ジチオトレイトール(DTT)緩衝液および全ての他の化学物質はSigma Aldrich(St.Louis、MOから購入し、384ウェル透明底プレートはCorning(Corning、NY)から購入した。
ザフィルルカストおよびモンテルカストは細胞外チオールイソメラーゼのチオールイソメラーゼの広範に使用可能な阻害剤であるので(実施例1を参照)、血小板をこの化合物を用いて処理した時に全体的な血小板応答の減少が予測される。
マウスにおける血栓形成に対するザフィルルカストの効果を精巣挙筋小動脈のレーザー損傷後に決定し、生体内顕微鏡法により観察した。雄C57/BL6マウスの血小板をDyLight 649共役抗GPIb抗体(0.2μg/g体重)を用いて標識し、ビヒクルまたはザフィルルカスト(ZFL)のいずれか(20μΜの循環濃度を達成するために必要とされる体積)を注入した。レーザー損傷後、画像を5分間記録した。図5は、ビヒクル処置マウス(n=18の血栓、丸)またはZFL処置マウス(n=12の血栓、四角)において形成された各血栓の最大蛍光強度を示し、ZFLを用いた処置は血栓サイズの低減を結果としてもたらすことを実証する。図6は、出血に対するZFLの効果を尾出血アッセイにより決定したことを示す。ビヒクルまたはZFL(20μΜの循環濃度を達成するために必要とされる体積)をC57/BL6マウスの大腿静脈に注入し、5分後に尾生検を行った。0.5cmの尾の先端を切除し、リン酸緩衝生理食塩水(PBS)中に血液を収集し、出血の中止までの時間を記録した。ZFLを用いた処置は出血時間の変化を伴わなかった。グラフは処置当たりn=10の平均±SEMを表し、データはスチューデントのT試験により解析した(***p<0.005)。
細胞を6,000細胞/ウェルにおいて96ウェルプレート中にプレートし、指し示した濃度のザフィルルカストを用いて24時間後に処理した。細胞をさらに24時間生育させた後、増殖の変化をPrestoBlue細胞増殖アッセイにより3連で測定した。570nmでの励起および600nmの発光を用いた蛍光読取りを収集し、処理した試料を非治療対照のパーセンテージに変換した。
HCTl16(ヒト結腸がん)細胞を薬物と共に24時間インキュベートし、総細胞抽出物を調製した。タンパク質レベルを標準化し、タンパク質をSDS−ポリアクリルアミドゲルに流した後に電気泳動させ、その後にPVDF膜に転写した。目的の一次抗体、その後にホースラディッシュペルオキシダーゼと共役させた二次抗体を用いて膜をプロービングした。ザフィルルカストを用いて処理したHCT116細胞のウエスタンブロットは、STAT3リン酸化の測定を通じてモニターしたEGFR活性化およびその下流のシグナル伝達のほぼ完全な阻害を示した。
Claims (19)
- 治療有効量の細胞外チオールイソメラーゼ阻害剤化合物を、それを必要とする患者に投与して、1つまたは複数の細胞外チオールイソメラーゼの活性により影響される疾患または状態を治療または予防することを含み、前記細胞外チオールイソメラーゼ阻害剤化合物が、ザフィルルカスト、モンテルカスト、アロセトロン、バルサラジド、ベンセラジド、ブタクラモール、レバドパ、メサラジン、オクスカルバゼピン、これらの薬学的に許容される塩、プロドラッグ、および/または固体状態形態である、方法。
- 前記細胞外チオールイソメラーゼの前記1つまたは複数のチオールイソメラーゼが、プロテインジスルフィドイソメラーゼ(PDI)、チオレドキシン、ERp5、ERp57、ERp72、またはこれらの組合せである、請求項1に記載の方法。
- 前記細胞外チオールイソメラーゼ阻害剤化合物がザフィルルカストである、請求項1または2に記載の方法。
- 前記疾患または状態が、動脈血栓症、静脈血栓症、血栓性疾患、がん、感染性疾患、ウイルス性疾患、免疫障害、炎症、神経学的疾患、神経変性障害、またはこれらの組合せである、請求項1〜3のいずれか1項に記載の方法。
- 前記疾患または状態が血栓症または血栓性疾患である、請求項1〜3のいずれか1項に記載の方法。
- 前記血栓性疾患が、急性心筋梗塞、安定狭心症、不安定狭心症、冠動脈形成術および/もしくはステント留置後の急性閉塞、一過性虚血発作、脳血管疾患、卒中、末梢血管疾患、胎盤不全、心房細動、深静脈血栓症、肺塞栓症、またはこれらの組合せである、請求項5に記載の方法。
- 前記疾患または状態ががんである、請求項1〜3のいずれか1項に記載の方法。
- 前記がんが、乳がん、結腸がん、大腸がん、神経膠腫、血液がん、喉頭がん、肺がん、リンパ腫、黒色腫、神経芽腫、卵巣がん、前立腺がん、またはこれらの組合せである、請求項7に記載の方法。
- 前記細胞外チオールイソメラーゼ阻害剤化合物が、薬学的に許容される担体を必要に応じてさらに含む医薬組成物として処方される、請求項1〜8のいずれか1項に記載の方法。
- 前記細胞外チオールイソメラーゼ阻害剤化合物が剤形中の医薬組成物として処方される、請求項1〜9のいずれか1項に記載の方法。
- 前記細胞外チオールイソメラーゼ阻害剤化合物が錠剤またはカプセルとして配合される、請求項10に記載の方法。
- 前記細胞外チオールイソメラーゼ阻害剤化合物が、経口的に、局所的に、非経口的に、吸入もしくはスプレーにより、舌下に、経皮的に、頬側投与を介して、または直腸内に投与するために好適な医薬組成物として処方される、請求項1〜10のいずれか1項に記載の方法。
- 前記患者に少なくとも1つの追加の治療剤を提供することをさらに含む、請求項1〜12のいずれか1項に記載の方法。
- 前記追加の治療剤が、抗血栓剤、抗凝固剤、化学療法剤、抗ウイルス剤、または抗炎症剤である、請求項13に記載の方法。
- 患者において血栓症、血栓性疾患、血小板凝集、フィブリン生成、またはこれらの組合せを予防または治療する方法であって、
治療有効量のザフィルルカストを、それを必要とする前記患者に投与することを含む、
方法。 - 動脈血栓症および静脈血栓症の予防または治療のための、請求項15に記載の方法。
- 1日に1回、2回、または3回投与される、約10〜約200mg、具体的には約20〜約175mg、より具体的には約40〜約150mg、およびよりいっそう具体的には約60〜約125mgの1日当たりの総用量のザフィルルカストを投与することを含む、請求項15または16に記載の方法。
- 細胞において細胞外チオールイソメラーゼのチオールイソメラーゼを阻害する方法であって、
前記細胞を有効量のザフィルルカスト、モンテルカスト、アロセトロン、バルサラジド、ベンセラジド、ブタクラモール、レバドパ、メサラジン、オクスカルバゼピン、これらの薬学的に許容される塩、プロドラッグ、および/または固体状態形態と接触させることを含む、方法。 - 前記細胞外チオールイソメラーゼの前記チオールイソメラーゼが、プロテインジスルフィドイソメラーゼ(PDI)、チオレドキシン、ERp5、ERp57、ERp72、またはこれらの組合せである、請求項18に記載の方法。
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