JP2008545718A - プロカスパーゼ−3の活性化を含む、癌細胞における選択的アポトーシス誘導 - Google Patents
プロカスパーゼ−3の活性化を含む、癌細胞における選択的アポトーシス誘導 Download PDFInfo
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Abstract
【選択図】 図4D
Description
[0001] 本出願は、2005年5月26日に提出された米国仮出願第60/684807号及び2006年3月28日に提出された米国仮出願第60743878号の米国特許法第119条(e)の下の利益を主張し、それぞれの全体が参照により援用される。
[0002] 本発明は、米国国立科学財団により与えられたNSF助成金/契約CHE−0134779の下、政府援助でなされた。政府は、本発明における一定の権利を有している。
[0003] アポトーシス又はプログラム細胞死はすべての多細胞生物の発生及びホメオスタシスで中心的な役割を果たしている(Shi Y,2002,Molecular Cell 9:459−470)。よくある癌の特徴は、本来のアポトーシスシグナルに対する抵抗性である。癌型によっては、この抵抗性は、通常、アポトーシスカスケードにおける重要なタンパク質のアップレギュレーション若しくはダウンレギュレーション又はこれらのタンパク質をコードする遺伝子内の変異による。上記変化は、ミトコンドリア及びカスパーゼ−9を経る内因性アポトーシス経路並びにデスレセプター及びカスパーゼ−8の作用が関与する外因性アポトーシス経路の両方で起こる。たとえば、p53、Bim、Bax、Apaf−1、FLIP、その他多くのタンパク質の適切なレベルの変化が癌で観察された。この変化は、欠陥のあるアポトーシスカスケードにつながる可能性があり、上流のアポトーシス促進シグナルが十分に伝達されず、実行因子カスパーゼであるカスパーゼ−3及びカスパーゼ−7が活性化されない。
[0011] 全体として、本明細書で使用される用語及び語句は、それらの技術的に認識された意味を有しており、当業者に知られている標準教科書、雑誌論文、及び文脈の参照により見つけることができる。
式中、n=1又は2であり、Rは、他のRとは独立して、水素、ハロゲン、アリル又は短鎖アルキルであり、R2=水素、短鎖アルキル、エステル、又は生理学的条件下で除去可能な他の部分であり、R3=水素、ハロゲン、アルキル、ハロアルキル、アリル、アルケニル、アルケノール、アルカノール又はハロアルケニルであり、R4及びR5は、いずれもNであるか、R4=N及びR5=Cであるか、R4及びR5=Cであり、A=酸素又は硫黄である。一実施形態では、上述の化合物は、式ZZ、PAC−1及び構造5から成る群より選択される。一実施形態では、上述の化合物はPAC−1である。
式中、n=1又は2であり、Rは、他のRとは独立して、水素、ハロゲン、アリル又は短鎖アルキルであり、R2=水素、短鎖アルキル、エステル、又は生理学的条件下で除去可能な他の部分であり、R3=水素、ハロゲン、アルキル、ハロアルキル、アリル、アルケニル、アルケノール、アルカノール又はハロアルケニルであり、R4及びR5は、いずれもNであるか、R4=N及びR5=Cであるか、R4及びR5=Cであり、A=酸素又は硫黄である。
式中、R1及びR2は、それぞれ、独立して、水素、ハロゲン、アルキル、アリル、ハロアルキル、アルケニル、アルケノール、アルカノール又はハロアルケニルである。一実施形態では、R1及びR2は、それぞれ、独立して、水素、ハロゲン、アリル又は短鎖アルキルである。
[0069] 以下の定義は、本発明の文脈中でのそれらの特定の用法を明確にするために提供される。
[0089] アポトーシスカスケードにおけるタンパク質の変異又は異常発現はよくある癌の特徴である。これらの変化は、アポトーシス促進シグナルが実行因子カスパーゼに伝達されるのを阻止し、したがってアポトーシス細胞死を阻止し細胞増殖が許可される可能性がある。カスパーゼ−3及びカスパーゼ−7は重要な実行因子カスパーゼであり、上流のシグナルにより活性化される不活性な酵素前駆体として存在する。重要なことには、プロカスパーゼ−3の発現レベルは、ある種の癌性細胞内では、非癌性対照に比べて著しく高度である。本明細書で、我々は、プロカスパーゼ−3を活性カスパーゼ−3に直接活性化する低分子の同定について報告する。特定の化合物であるPAC−1は、約220ナノモル濃度の桁でEC50のin vitroでの活性化を引き起こし、多数の癌性細胞株におけるアポトーシスを誘導する。
[00104] 材料:Ni−NTA樹脂及び抗Penta His Alexa Fluor 647抗体はQiagen社(バレンシア、CA)から購入した。ブラッドフォード染料はBio−Rad社(ハーキュリーズ、CA)から購入した。ピン移動装置はV&P Scientific社(サンディエゴ、CA)から購入した。試薬z−vad−fmkはCalbiochem社(サンディエゴ、CA)から購入した。大腸菌RosettaはNovagen社(マディソン、WI)から購入した。抗カスパーゼ−3抗体はSigma社(セントルイス、MO)から購入した。アネキシンV Alexa Fluor 488複合体、JC−9、及びヨウ化プロピジウムはMolecular Probes社(ユージーン、OR)から購入した。IPTG及びMTS/PMS CellTiter 96細胞増殖アッセイ試薬はPromega社(マディソン、WI)から購入した。ウシ胎児血清はBiomeda社(フォスターシティ、CA)から購入した。96及び384ウェルマイクロタイタープレート、顕微鏡用スライドガラス、顕微鏡用カバーガラス、ウマ血清、並びに他のすべての試薬はFisher社(シカゴ、IL)から購入した。
[00124] PAC−1及び他の化合物は、以下のスキーム、たとえば下記スキーム1及び/又はスキーム2に従って調製した。さらなる変形形態は、当技術分野で知られている方法に従って調製する。
[00127] 以下は、医薬品実施形態及び薬理学的実施形態に関連する情報を記載し、当業者にとって入手可能な当技術分野における情報によりさらに補足される。厳密な処方、投与経路、及び用量は、個々の医師が、患者の症状を考慮して選択することができる(たとえばFinglら,in The Pharmacological Basis of Therapeutics,1975,Ch.1 p.1参照)。
[00140] 要約:アポトーシスカスケードにおけるタンパク質の変異又は異常発現は癌の特徴である。これらの変化は、アポトーシス促進シグナルが実行因子カスパーゼに伝達されるのを阻止し、したがってアポトーシス細胞死を阻止し、細胞増殖が許可される。カスパーゼ−3及びカスパーゼ−7は重要な実行因子カスパーゼであり、上流のシグナルにより活性化される不活性な酵素前駆体として存在する。重要なことには、プロカスパーゼ−3のレベルは非癌性対照に比べてある種の癌性細胞内で著しく高度である。本明細書で、我々は、プロカスパーゼ−3を活性カスパーゼ−3に220ナノモル濃度のEC50でin vitroで直接活性化し、様々な癌細胞株におけるアポトーシスを誘導する低分子(PAC−1)の同定について報告する。多くの知られている抗癌薬とは対照的に、PAC−1で処置した細胞はプロカスパーゼ−3の即時活性化を示し、PAC−1の有効性は、細胞に含まれるプロカスパーゼ−3の量に比例することが示される。in vitroでプロカスパーゼ−3を活性化しないPAC−1の誘導体はアポトーシス促進活性も有していない。一次大腸腫瘍から単離した癌性細胞は、同一患者からの隣接した非癌性組織の細胞よりも、PAC−1によるアポトーシス誘導にかなりの感受性がある。これらの癌性細胞は、隣接した非癌性一次組織の細胞よりも平均して約7倍のプロカスパーゼ−3を含んでいる。さらに、大腸癌腫瘍からの一次細胞のPAC−1に対する感受性は、プロカスパーゼ−3標的のレベルと強く関連している。最終的に、単一の実体としてのPAC−1は、PAC−1を経口的に投与した2つのモデルを含む3つの異なるマウスモデルにおいて腫瘍の成長を遅延させるのに活性のあるものとして示された。したがって、PAC−1は、生体内で、プロカスパーゼ−3をカスパーゼ−3に直接活性化し、それによって、欠陥のあるアポトーシス機構を有する細胞においてでさえこの化合物がアポトーシスを誘導することを可能にする。PAC−1は、プロカスパーゼ−3を直接活性化することで知られている最初の低分子であり、実行因子カスパーゼの直接的な活性化は、プロカスパーゼ−3レベルが上昇した多くの癌において有利であると証明することが可能である抗癌戦略である。
[00161] 図1及び図2:PAC−1の構造は明細書の他のところで示す。図1A)in vitroでのPAC−1によるプロカスパーゼ−3の活性化及び活性カスパーゼ−3。PAC−1は、EC50=0.22μMでプロカスパーゼ−3を活性化する。図1B)PAC−1により誘導される活性カスパーゼ−3へのプロカスパーゼ−3の切断。プロカスパーゼ−3をN末端His−6タグを用いて大腸菌中で組換え発現させ、精製した。免疫ブロットは抗His−6抗体を用いて行った。PAC−1非存在下でプロカスパーゼ−3の成熟は観察されない。100μM PAC−1存在下で、p19フラグメントを生成する切断が1時間以内に観察され、>50%の切断が4時間後に観察される。PAC−1はまた、このアッセイにおいて5μMでも有効である。図2A)プロカスパーゼ−3の「安全装置」領域における変異体のPAC−1による活性化。PAC−1は、野性型プロカスパーゼ−3(DDD)に対して0.22μMの活性化のためのEC50並びに変異体については2.77μM(DAD)、113μM(DDA)、及び131μM(ADD)の対応するEC50値を有している。図2B)PAC−1は、4.5μMのEC50でプロカスパーゼ−7を活性化する。図2C)プロカスパーゼ−3のPAC−1による活性化についてのpHへの依存性。低pHでは、安全装置はオフの状態にあり、プロカスパーゼ−3は本質的に最大限に活性化される。エラーバーは、平均値からの標準偏差を表す。
[00165] NCI−H226(肺癌)細胞を使用して、異種移植モデルを用いた。PAC−1を腹腔内に(i.p.)10mg/kg与えた。40mg/kgのゲフィチニブ(イレッサ(商標);アストラゼネカ社、ウィルミントン、デラウェア)を用い、グループ当たり5匹のマウスを使用して有効性の比較を行った。図7に結果を示すが、結果は、PAC−1が、腫瘍容積という点で成長を低下させることと関連したことを示す。
[00166] 多くの化合物をPAC−1構造の誘導体として調製する。ヒドラジド基をアルデヒド基と反応させ、誘導体化合物のコンビナトリアルライブラリーを得る。
[00171] PAC−1及びある種の誘導体をHL−60細胞株で試験し、IC50値を測定した。表5に結果を示す(L−及びR−の指定は上記のAX及びBXのシリーズに示した構造をそれぞれ指す)。PAC−1誘導体のいくつかは、概してPAC−1化合物の活性レベルよりも約1桁大きい活性レベルを示した。
[00172] 本出願にわたるすべての参考文献、たとえば発行された若しくは許可された特許又は均等物を含む特許文献、特許出願公開、非公開特許出願、及び非特許文献又は他の資料は、それぞれの参考文献が本出願における本開示と少なくとも部分的に矛盾していない程度に個々に引用されるように(たとえば、部分的に矛盾した参考文献の部分を除いて、部分的に矛盾した参考文献が参照により援用される)、これによってそれらの全体が参照により本明細書中に援用される。
[00176] 次の出願は、特に、その全体が参照により援用される。2003年10月30日に提出されたHergenrotherらによる米国仮特許出願第60/516556号;2004年8月20日に提出されたHergenrotherらによる米国仮特許出願第60/603246号;2004年10月27日に提出されたHergenrotherらによる米国特許出願第10/976186号。
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Claims (44)
- 癌細胞におけるアポトーシスを選択的に誘導する方法であって、
(a)前記癌細胞のプロカスパーゼ−3分子を修飾することができる化合物を当該癌細胞に投与するステップと、
(b)アポトーシスを誘導するように前記プロカスパーゼ−3分子を修飾するステップと、を含む方法。 - 前記癌細胞が、処置を必要とする患者に存在する、請求項1に記載の方法。
- 前記化合物が、式ZZ、PAC−1及び構造5から成る群より選択される、請求項1〜3のいずれか一項に記載の方法。
- 前記化合物がPAC−1である、請求項1〜3のいずれか一項に記載の方法。
- 癌細胞におけるプロカスパーゼ−3又はカスパーゼ−3のパラメーターを評価するステップをさらに含み、
前記パラメーターが、半定量的若しくは定量的な量、機能的な量、又は前記プロカスパーゼ−3若しくはカスパーゼ−3の活性レベル、の1つ又は複数である、請求項1〜3のいずれか一項に記載の方法。 - プロカスパーゼ−3分子を修飾することができる化合物を直接、in vitroでスクリーニングするための方法であって、
(a)試験化合物を提供するステップと、
(b)精製したプロカスパーゼ−3を提供するステップと、
(c)前記精製したプロカスパーゼ−3に前記試験化合物を暴露するステップと、
(d)前記試験化合物への暴露の後でプロカスパーゼ−3活性を測定するステップと、
(e)前記試験化合物への前記暴露の際の試験活性を、前記試験化合物への暴露なしでの無修飾活性と比較することにより、修飾化合物を同定するステップと、を含み、
それにより、プロカスパーゼ−3分子を修飾することができる化合物をスクリーニングする方法。 - 前記修飾活性又は前記無修飾活性を基準活性と比較するステップをさらに含み、
前記基準活性が、構造式ZZ、PAC−1及び構造5から成る群より選択される化合物への暴露によるものである、請求項9に記載の方法。 - プロカスパーゼ−3分子を修飾することができる化合物の細胞スクリーニングのための方法であって、
(a)試験化合物を提供するステップと、
(b)プロカスパーゼ−3を推定上発現する細胞を提供するステップと、
(c)前記試験化合物に前記細胞を暴露するステップと、
(d)前記試験化合物への暴露の後で、細胞生存率、アポトーシス指標、及び他のパラメーターを含む細胞パラメーターの、1つ又は複数を測定するステップと、
(e)前記試験化合物への前記暴露の際の試験細胞パラメーターを、前記試験化合物への暴露なしでの無修飾細胞パラメーターと比較することにより、修飾化合物を同定するステップと、を含み、
それにより、プロカスパーゼ−3分子を修飾することができる化合物をスクリーニングする方法。 - 前記修飾活性又は前記無修飾活性を基準活性と比較するステップをさらに含み、
前記基準活性が、ZZ、PAC−1及び構造5から成る群より選択される化合物への暴露によるものである、請求項11に記載の方法。 - プロカスパーゼ活性化化合物による癌細胞の処置に対する潜在的感受性を同定又は診断するための方法であって、
(a)前記癌細胞内のプロカスパーゼパラメーターを評価するステップと、
(b)前記パラメーターによりプロカスパーゼの活性化に対する感受性が上昇したかどうかを判定するステップと、を含む方法。 - 前記プロカスパーゼパラメーターがプロカスパーゼ−3レベルであり、前記プロカスパーゼがプロカスパーゼ−3である、請求項13に記載の方法。
- 前記プロカスパーゼパラメーターがプロカスパーゼ−7レベルであり、前記プロカスパーゼがプロカスパーゼ−7である、請求項13に記載の方法。
- 癌細胞を処置するための方法であって、
(a)プロカスパーゼ活性化化合物による癌細胞の処置に対する潜在的感受性を同定するステップと、
(b)有効な量の前記プロカスパーゼ活性化化合物に前記癌細胞を暴露するステップと、を含む方法。 - 前記プロカスパーゼ活性化化合物が、式ZZ、PAC−1及び構造5から成る群より選択される、請求項16に記載の方法。
- 前記プロカスパーゼ活性化化合物が、プロカスパーゼ−3、プロカスパーゼ−7、又はプロカスパーゼ−3及びプロカスパーゼ−7の両方を活性化することができる、請求項16又は17に記載の方法。
- PAC−1を合成するための方法であって、
スキーム1のステップを含む方法。 - 化合物5又は式ZZの化合物を合成するための方法であって、
適切な変更を有するスキーム1のステップを含む方法。 - R1及びR2が、それぞれ、独立して、水素、ハロゲン、アリル又は短鎖アルキルである、請求項22に記載の化合物。
- アルデヒド化合物と結合したヒドラジド化合物を含むPAC−1誘導体コンビナトリアルライブラリーから成る群より選択される化合物。
- 前記ヒドラジド化合物が、本明細書中に記載されたAX化合物から生成されたヒドラジドから成る群より選択され、
前記アルデヒド化合物が、本明細書中に記載されたBX化合物から成る群より選択される、請求項24に記載の化合物。 - PAC−1誘導体化合物を合成するための方法であって、
ヒドラジド化合物を提供するステップと、
アルデヒド化合物を提供するステップと、
前記ヒドラジド化合物を前記アルデヒド化合物と反応させるステップと、を含み、
それによりPAC−1誘導体化合物を合成する方法。 - 前記ヒドラジド化合物が前記式ZZ3を有し、
前記アルデヒド化合物が前記式ZZ4を有する、請求項26〜28のいずれか一項に記載の方法。 - L01R06、L02R03、L02R06、L08R06、L09R03、L09R06及びL09R08から成る群より選択される化合物。
- 癌患者の候補者を、前記候補者においてプロカスパーゼレベルの上昇を同定することにより、プロカスパーゼ活性化剤による可能な処置についてスクリーニングするための方法であって、
前記候補者から細胞又は組織の試験サンプルを得るステップと、
前記試験サンプル中のプロカスパーゼレベルを評価するステップと、
前記プロカスパーゼレベルが、基準レベルに比べて前記試験サンプル中で上昇したかどうかを判定するステップと、を含み、
それにより、癌患者の候補者を、プロカスパーゼ活性化剤による可能な処置についてスクリーニングする方法。 - 前記プロカスパーゼが、プロカスパーゼ−2、プロカスパーゼ−3、プロカスパーゼ−6、プロカスパーゼ−7、プロカスパーゼ−8及びプロカスパーゼ−9から成る群より選択される、請求項31に記載の方法。
- 前記プロカスパーゼがプロカスパーゼ−3である、請求項31又は32に記載の方法。
- 前記試験サンプルの前記上昇レベルが、前記基準レベルの少なくとも約2倍である、請求項31〜33のいずれか一項に記載の方法。
- 前記試験サンプルの前記上昇レベルが、前記基準レベルの少なくとも約4倍である、請求項31〜34のいずれか一項に記載の方法。
- 前記基準レベルが、同一患者からの第2の試験サンプルからのものである、請求項31〜35のいずれか一項に記載の方法。
- 前記基準レベルが、正常細胞又は正常組織のサンプルからのものである、請求項31〜36のいずれか一項に記載の方法。
- 前記基準レベルが細胞株からのものである、請求項31〜37のいずれか一項に記載の方法。
- 前記基準レベルが癌細胞株からのものである、請求項31〜38のいずれか一項に記載の方法。
- 前記基準レベルが正常細胞株からのものである、請求項31〜39のいずれか一項に記載の方法。
- 前記基準レベルが絶対閾値の量である、請求項31〜40のいずれか一項に記載の方法。
- 癌細胞における死を誘導するための方法であって、
当該癌細胞のプロカスパーゼ−3分子を活性化することができる化合物を当該癌細胞に投与するステップを含む方法。 - 前記化合物が構造式ZZを有する、請求項42に記載の方法。
- 前記化合物が構造式ZZ2を有する、請求項42に記載の方法。
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US11/420,425 US20070049602A1 (en) | 2005-05-26 | 2006-05-25 | Selective Apoptotic Induction in Cancer Cells Including Activation of Procaspase-3 |
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JP2015511956A (ja) * | 2012-03-02 | 2015-04-23 | ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティー オブ イリノイ | 二重複合活性化による強力な抗癌活性 |
JP2017517522A (ja) * | 2014-05-30 | 2017-06-29 | インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー.エル.エー.チャイナ | 置換アセチドラジド誘導体、その調製方法及び使用 |
JP2018521142A (ja) * | 2015-07-23 | 2018-08-02 | ワン,チミン | 化合物pac−1またはその塩及びそれらを含有する医薬組成物 |
JP2018525436A (ja) * | 2015-07-24 | 2018-09-06 | シェンチェン インスティチュート オブ シィァンヤー バイオメディシン | オービットアジン−フマル酸塩、水和物、結晶形及びその調製方法 |
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US20070049602A1 (en) * | 2005-05-26 | 2007-03-01 | The Board Of Trustees Of The University Of Illinois | Selective Apoptotic Induction in Cancer Cells Including Activation of Procaspase-3 |
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US8916705B2 (en) | 2011-10-14 | 2014-12-23 | The Board of Trustees of The University of Illilnois | Procaspase-activating compounds and compositions |
MX364002B (es) * | 2012-08-03 | 2019-04-10 | Univ Illinois | Compuestos y composiciones activadoras de enzima. |
US10350207B2 (en) | 2015-06-05 | 2019-07-16 | The Board Of Trustees Of The University Of Illinois | PAC-1 combination therapy |
CN105085421B (zh) * | 2015-07-24 | 2017-12-26 | 深圳市湘雅生物医药研究院 | 奥比特嗪‑富马酸盐、水合物、晶型及其制备方法 |
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