JP6449764B2 - Pin1の阻害のための方法および組成物 - Google Patents
Pin1の阻害のための方法および組成物 Download PDFInfo
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- JP6449764B2 JP6449764B2 JP2015516246A JP2015516246A JP6449764B2 JP 6449764 B2 JP6449764 B2 JP 6449764B2 JP 2015516246 A JP2015516246 A JP 2015516246A JP 2015516246 A JP2015516246 A JP 2015516246A JP 6449764 B2 JP6449764 B2 JP 6449764B2
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Description
本出願は、2012年6月7日付け出願の米国仮特許出願第61/656,806号(その全体を参照により本明細書に組み入れることとする)の利益を主張するものである。
本発明は助成番号NIH R03DA031663およびR01CA167677の米国政府の支援によりなされた。米国政府は本発明における一定の権利を有する。
一般に、本発明は、Pin1を阻害するための組成物および方法、ならびにPin1レベルの上昇により特徴づけられる障害(例えば、免疫障害および増殖障害)の、本明細書中に定められている化合物による治療に関する。
R1、R2、R3およびR4のそれぞれは、独立して、H、所望により置換されていてもよいC1-C6アルキル、OH、所望により置換されていてもよいC1-C6アルコキシ、ハロゲン、ニトロ、所望により置換されていてもよいC1-C6アシル、またはCO2R10である;
R5、R6およびR10のそれぞれは、独立して、Hまたは所望により置換されていてもよいC1-C6アルキルである;
R7aおよびR7bは共にHであり、あるいはR7aとR7bとは一緒になって、炭素-炭素二重結合を形成している;
R8およびR9のそれぞれは、独立して、H、所望により置換されていてもよいC1-C6アルキル、OH、所望により置換されていてもよいC1-C6アルコキシ、所望により置換されていてもよいアリールオキシ、SH、所望により置換されていてもよいチオアリールオキシ、ハロゲン、所望により置換されていてもよいC1-C6アシルである]の構造を有し、またはその立体異性体またはその医薬上許容される塩である。
nは0、1、2、3または4である;
各R1は、存在する場合には、独立して、所望により置換されていてもよいC1-C6アルキル、OH、所望により置換されていてもよいC1-C6アルコキシ、ハロゲン、ニトロまたは所望により置換されていてもよいC1-C6アシルである;
R2はHまたは所望により置換されていてもよいC1-C6アルキルである;
R3aおよびR4bは共にHであり、あるいはR3aとR3bとは一緒になって、炭素-炭素二重結合を形成している;
R4およびR5は共にHであり、あるいはR4とR5とは一緒になって、炭素-炭素二重結合を形成している;
R6は、所望により置換されていてもよいフェニルである;
R7は、所望により置換されていてもよいC1-C6アルキルである]の構造を有し、またはその立体異性体またはその医薬上許容される塩である。
R1およびR2の一方はHであり、もう一方は-NH(所望により置換されていてもよいフェニル)であり、そしてR3、R4、R5およびR6は、独立して、H、OR7またはSO3R8である;
R7およびR7のそれぞれは、独立して、Hまたは所望により置換されていてもよいC1-C6アルキルであり、そして、ここで、R3、R4、R5およびR6の1つ及びただ1つはSO3R8であり、そして、ここで、R3、R4、R5およびR6の1つ及びただ1つはOR7である]の構造を有し、またはその立体異性体またはその医薬上許容される塩である。
R1およびR2のそれぞれは、独立して、所望により置換されていてもよいC1-C6である;
Aは、部分構造CO2R3のカルボキシル置換基を含むフェニルまたは5員ヘテロアリールであり、そして、ここで、Aは0、1、2または3個の置換基を含む]の構造を有し、またはその立体異性体またはその医薬上許容される塩である。
R1はCNまたはC(=O)R3である;
R2およびR3のそれぞれは、独立して、所望により置換されていてもよいフェニルまたは所望により置換されていてもよい5〜6員ヘテロアリールである]の構造を有し、またはその立体異性体またはその医薬上許容される塩である。
本発明者らは、Pin1を阻害するのに有用な化合物(すなわち、表1の化合物)を本発明において見出した。Pin1のインヒビターは、免疫障害および増殖性障害(例えば、Pin1マーカーレベルの上昇により特徴づけられる障害)を治療するのに有用である。他の好ましい実施形態においては、表1の化合物は、加齢関連障害、喘息および微生物感染症を有する対象への投与に有用である。前記疾患の治療におけるPin1インヒビターの有用性はPCT出願番号PCT/US2012/029077、PCT/US2012/35473、PCT/US2012/39850、PCT/US2010/054077、米国特許出願公開第2008/0214470 A1号、米国特許第6,495,376 B1号、第6,462,173 B1号、第8,129,131 B2号、第8,258,099 B2号、および米国仮特許出願第61/490,338号(それらのそれぞれの全体を具体的に参照により本明細書に組み入れることとする)に更に特定されており、または詳細に記載されている。
セリン/トレオニン-プロリンモチーフ上のリン酸化はシス/トランス・プロリル異性化を抑制し、そしてまた、必須タンパク質Pin1のための結合部位を生成する。Pin1はリン酸化タンパク質の所定の一部のものに結合し、それらの活性を調節し、分裂進行のタイミングに関与する。構造的および機能的な両方の分析が、リン酸化タンパク質に結合するホスホセリン/トレオニン結合性モジュールと、リン酸化ホスホセリン・トレオニン-プロリンを特異的に異性化する触媒活性とを、Pin1が含有することを示している。Pin1がその機能をインビボで行うためには、これらのPin1活性の両方が必須である。
Pin1インヒビターを特定する多数の方法が当技術分野で公知である。Pin1インヒビターを特定する1つの方法においては、候補または試験化合物は、Pin1タンパク質またはそのポリペプチドもしくは生物学的に活性な部分に結合しうる、Pin1タンパク質またはそのポリペプチドもしくは生物学的に活性な部分の基質である。Pin1インヒビターを特定するもう1つの方法においては。
本発明は、Pin1マーカーレベルの上昇と併発するものとして特定される障害の、表1の化合物での治療に関する。幾つかの態様においては、本発明は、対象においてPin1マーカーレベルを決定し、ついで、Pin1マーカーレベルが上昇していると決定された対象において表1の化合物を投与することに関する。他の態様においては、本発明はまた、免疫障害または増殖性障害の治療における療法の進行を評価するために、表1の化合物の投与の後でPin1マーカーレベルを測定することに関するものでありうる。
生物学的サンプルにおけるPin1タンパク質または核酸の存在または非存在を検出するための典型的な方法は、生物学的サンプルを試験対象から得、該生物学的サンプルを、Pin1タンパク質またはPin1タンパク質をコードする核酸(例えば、mRNA、ゲノムDNA)を検出しうる化合物または物質と接触させて、該生物学的サンプルにおいてPin1タンパク質または核酸の存在を検出することを含む。Pin1 mRNAまたはゲノムDNAを検出するための好ましい物質は、Pin1 mRNAまたはDNAにハイブリダイズしうる標識核酸プローブである。該核酸プローブは、例えば、Pin1核酸、または対応核酸、例えば、ストリンジェントな条件下でPin1 mRNAまたはゲノムDNAに特異的にハイブリダイズしうる少なくとも15、30、50、100、250または500ヌクレオチド長のオリゴヌクレオチドでありうる。本発明の診断アッセイにおいて使用される他の適当なプローブは本明細書に記載されている。
本明細書に記載されている診断方法は更に、異常なPin1発現または活性に関連した疾患または障害を有する或いは該疾患または障害を発生するリスクを有する対象を特定するために使用されうる。例えば、本明細書に記載されているアッセイ(例えば、前記診断アッセイまたは後記アッセイ)は、Pin1マーカーに関連した障害(例えば、免疫障害または増殖性障害)を有する或いは該障害を発生するリスクを有する対象を特定するために使用されうる。したがって、本発明は、異常なPin1発現または活性に関連した疾患または障害を特定するための方法を提供し、この場合、対象から試験サンプルを得、Pin1タンパク質または核酸(例えば、mRNA、ゲノムDNA)を検出し、ここで、Pin1タンパク質または核酸の存在は、Pin1関連障害を有する又は該障害を発生するリスクを有する対象の診断をもたらし、したがって、表1の化合物での治療に対して感受性である。
1つの実施形態においては、本発明は、表1の化合物での対象の治療の有効性をモニターするための方法に関する。該方法は、(i)該化合物の投与の前に対象から投与前サンプルを得、(ii)該投与前サンプルにおけるPin1タンパク質、Ser71上のPin1リン酸化、mRNA、ゲノムDNAまたは他のPin1マーカーの発現または活性のレベルを検出し、(iii)該対象から1以上の投与後サンプルを得、(iv)該投与後サンプルにおけるPin1タンパク質、mRNAまたはゲノムDNAの発現または活性のレベルを検出し、(v)該投与前サンプルにおけるPin1タンパク質、mRNAまたはゲノムDNAの発現または活性のレベルを該投与後サンプルにおけるPin1タンパク質、mRNA、ゲノムDNAまたは他のPin1マーカーと比較し、(vi)それに応じて、該対象への表1の化合物の投与を改変する工程を含む。そのような実施形態においては、Pin1の発現、リン酸化または活性は、観察可能な応答の非存在下であっても、表1の化合物の有効性の指標として用いられうる。
本発明のインヒビターは、有効成分としてのPin1インヒビターの有効量を含有する組成物へと製剤化(処方)されうる。そのような組成物は医薬上許容される担体をも含むことが可能であり、本明細書においては医薬組成物と称される。本発明のインヒビター組成物は静脈内に、非経口的に、経口的に、吸入により、または坐剤により投与されうる。本発明の製剤は、経口、鼻腔内、局所、経皮、頬側、舌下、直腸、膣および/または非経口投与に適したものを含む。該製剤は単位投与形として簡便に提供されることが可能であり、薬学分野でよく知られたいずれかの方法により調製されうる。単一剤形を製造するために担体物質と組合されうる有効成分の量は、一般に、治療効果をもたらす化合物の量である。一般に、100%のうち、この量は約1〜約99%、好ましくは約5%〜約70%、最も好ましくは約10%〜約30%の有効成分の範囲である。該インヒビター組成物は、所望の効果をもたらすのに十分なインヒビターのレベルが得られるように、或る期間にわたって、2以上の用量で、または単一用量で投与されうる。
本発明は、Pin1発現または活性の上昇に関連した障害のリスクを有する(または該障害に感受性である)または該障害に罹患した対象を表1の化合物で治療する治療方法および予防方法の両方を提供する。
1つの態様においては、本発明は、表1の化合物を対象に投与することによる、対象における免疫障害または増殖性障害の予防方法を提供する。異常なPin1の発現または活性により引き起こされる又はそれが関与する疾患のリスクを有する対象は、例えば、本明細書に記載されている診断または予後アッセイのいずれか又は組合せにより特定されうる。表1の化合物の投与は、疾患または症状が予防され、および/またはその進行が遅れるように、Pin1の異常に特徴的な症状の発現の前に行われうる。
免疫障害または増殖性障害を治療するためには、本発明の表1の化合物と組合された抗炎症剤が有用である。表1の化合物と組合せて使用されうる抗炎症剤には、限定的なものではないが、コルチコステロイド、NSAID(例えば、ナプロキセンナトリウム、ジクロフェナクナトリウム、ジクロフェナクカリウム、アスピリン、スリンダク、ジフルニサル、ピロキシカム、インドメタシン、イブプロフェン、ナブメトン、トリサリチル酸コリンマグネシウム、サリチル酸ナトリウム、サリチルサリチル酸(サルサラート)、フェノプロフェン、フルルビプロフェン、ケトプロフェン、メクロフェナム酸ナトリウム、メロキシカム、オキサプロジン、スリンダクおよびトルメチン)、COX-2インヒビター(例えば、ロフェコキシブ、セレコキシブ、バルデコキシブおよびルミラコキシブ)、生物製剤(例えば、インフリキシマブ、アデリムマブ、エタネルセプト、CDP-870、リツキシマブおよびアトリズマブ)、小分子免疫モジュレーター(例えば、VX 702、SCIO 469、ドラマピモド、RO 30201195、SCIO 323、DPC 333、プラナルカサン、ミコフェノラートおよびメリメポジブ)、非ステロイド性イムノフィリン依存性免疫抑制剤(例えば、シクロスポリン、タクロリムス、ピメクロリムスおよびISAtx247)、5-アミノサリチル酸(例えば、メサラミン、スルファサラジン、バルサラジド二ナトリウムおよびオルサラジンナトリウム)、DMARD(例えば、メトトレキサート、レフルノミド、ミノサイクリン、オーラノフィン、金チオリンゴ酸ナトリウム、アウロチオグルコースおよびアザチオプリン)、硫酸ヒドロキシクロロキンおよびペニシラミンが含まれる。
本明細書に記載されているPin1インヒビターは、異常なPin1活性に関連した障害(例えば、増殖性障害、例えば、癌)を(予防的または治療的に)治療するために個体に投与されうる。そのような治療に関しては、薬理ゲノミクス(すなわち、個体の遺伝子型と外来化合物または薬物に対するその個体の応答との間の関係の研究)が考慮されうる。治療用物質の代謝における相違は、用量と薬理学的に活性な薬物の血中濃度との関係を変化させることにより、重篤な毒性または治療の失敗をもたらしうる。したがって、医師または臨床家は、Pin1インヒビターを投与すべきかどうかの決定、ならびにPin1分子もしくはPin1分子での治療の投与量および/または治療レジメンを適合化する際に、関連する薬理ゲノミクス研究において得られた知見の適用を考慮しうる。
本発明のインヒビターは、真核細胞の増殖を妨げるために使用されうる。該インヒビターは、細胞周期調節、有糸分裂事象、タンパク質分解、アポトーシス、神経変性疾患、または細胞分裂の或る態様、例えば胚発生、またはそれらのシグナル伝達経路を研究するために、インビトロで使用されうる。該インヒビターは、発癌につながる経路の決定において、または転移性癌における細胞拡散のような事象を評価し、妨げ、もしくは治療するために使用されうる。該インヒビターは、細胞増殖を抑制するために、および標的化細胞を死亡させるために使用されうる。例えば、本発明のインヒビターは、家畜およびヒトのような哺乳動物において、アスペルギルス(Aspergillus)を含む真菌または酵母の増殖および寄生虫感染(例えば、マラリア)を妨げるために使用されうる。
(実施例)
VIII.実験結果
実施例1.Pin1インヒビターアッセイ
Pin1のインヒビターの特定のためのアッセイを開発した。このアッセイの目的は、蛍光偏光競合アッセイ(図1)を用いてPin1の小分子インヒビターを特定することであった。このアッセイにおいては、与えられた候補小分子阻害化合物が、Pin1の活性部位に通常は結合するHiFluor-488標識ペプチドを置換するかどうかを決定するために、蛍光偏光を用いる。候補化合物を濃度-滴定系列(例えば、57μM〜0.7nM)においてスクリーニングした。
実施例1のPin1蛍光偏光競合アッセイを用いて、393,181個の化合物のライブラリーからPin1のインヒビターを特定した(表3)。オフラインLOPACアッセイにおいて初期分析を行った。1,280個の化合物を含む10個のプレートをスクリーニングして、8,960個のデータ点を集めた。1.8%のヒット率が得られた。30プレートの後続のオンラインLOPAC分析も1,280個の化合物を含み、26,880個のデータ点を集めた。1.5%のヒット率が得られた。ついで393,181個の化合物の1607個のプレートのqHTSを行い、2,359,086個のデータ点を集めた。0.6%のヒット率が得られた(表3)。プレートごとのS:B比、プレートごとのZ'スコア、またはプレートごとのCV%を用いて、該アッセイの性能が評価されうる(図2)。
実施例2のPin1蛍光偏光競合アッセイから集められたデータは、変化した偏光蛍光または全蛍光による、化合物の対数濃度(X軸)を示す曲線として表されうる(図3A〜3E)。偏光蛍光の変化を示す曲線は5つのクラスに分類されうる。クラス1は、>80%(クラス1.1)または<80%(クラス1.2)の効力を有する、2本の漸近線および>0.9のr2値を有する完全曲線を含む。クラス1の曲線は、効力が>80%およびr2<0.9である場合(クラス1.3)または効力が<80%およびr2<0.9である場合(クラス1.4)、ノイズ性(noisy)曲線としても分類されうる。クラス2は、>80%(クラス2.1)または<80%(クラス2.2)の効力を有する、1本の漸近線および>0.9(サブクラスa)または<0.9(サブクラスb)のr2値を有する不完全な曲線を含む。クラス2の曲線は、効力が>80%およびr2<0.9である場合(クラス2.3)または効力が<80%およびr2<0.9である場合(クラス2.4)、ノイズ性(noisy)曲線としても分類されうる。クラス3は、最高試験濃度におけるサンプル領域の平均活性からの効力>3SDおよび1本の漸近線を有する単点活性曲線を含む。クラス4は、漸近線が存在せず、効力およびr2値が適用可能でない不活性曲線を含む。第5のクラスは、それ以外では分類されないいずれかの曲線を捕捉する(図4)。
実施例3において分析されたとおりに実施例2のPin1蛍光偏光競合アッセイにおいて特定されたPin1インヒビターを更に評価するために、1198個の特定されたPin1インヒビターのうちの1086個を確認Pin1蛍光偏光競合アッセイにおいて再試験した。1086個の化合物のうちの307個がクラス1.1、1.2、2.1または2.2曲線および50%を超える効力を示した。
Pin1インヒビターを特定するためのハイスループットスクリーニングを、一工程蛍光偏光置換アッセイ(FP-HTS)を用いて開発した。FP-HTSは、触媒活性部位に結合する基質に関して競合する分子を検出し、平衡条件下のリガンド結合を測定し、産物阻害を受けない。FPアッセイのためのHF488蛍光プローブは、Pin1に対する258nMのKdを有する、Bth-L-ホス.Thr-Pip-Nal (pTide)の僅か4個の残基コア構造を含有する(Anaspecにより合成された)。本発明者らは、Synergy IIプレートリーダーを使用し、plate完全長Pin1を使用して、384ウェルプレートフォーマットにおいて、FP-HTSを行い、偏光度の値における6〜7倍の増加を示すロウバスト(頑強)なFPを得た。この新規FP-HTSはロウバストかつ再現可能な性能を示した。該アッセイは10%までのDMSOに耐えうる。Z'は約0.70であり、日々の性能に関して一貫している。変動係数は4〜5%の範囲である。より重要なことに、本発明者らは、この計画における陽性対照としての非標識Pin1ペプチドであるpTide、およびPin1小分子インヒビターであるジュグロンが共に、HF488プローブをPin1から置換したことを示している。共有的および不可逆的インヒビターであるジュグロンのKdを決定することは困難であるが、pTideのKdは-250nMであった。これは、PPIアーゼに基づくアッセイから導き出されたものに類似している。
本明細書中に挙げられている全ての刊行物、特許および特許出願を、各個の刊行物または特許出願が参照により本明細書に組み入れられると具体的かつ個別に示されている場合と同様に、参照により本明細書に組み入れることとする。
[1] Pin1を表1の化合物と接触させることによりPin1を阻害する方法。
[2] 該Pin1が細胞内に存在する、1記載の方法。
[3] 該細胞がヒト細胞である、1記載の方法。
[4] 免疫障害の治療を要する対象に表1の化合物の治療的有効量を投与する工程を含む、対象における免疫障害の治療方法。
[5] 増殖性障害の治療を要する対象に表1の化合物の治療的有効量を投与する工程を含む、増殖性障害の治療方法。
[6] 該対象が該投与の前にPin1マーカーのレベルの上昇を有すると決定される、4〜5のいずれか1項記載の方法。
[7] 対象からのサンプルにおけるPin1マーカーレベルを決定し、該対象からのサンプルがPin1マーカーレベルの上昇を有すると決定された場合に、表1の化合物の治療的有効量を該対象に投与する工程を含む、対象における免疫障害の治療方法。
[8] 対象からのサンプルにおけるPin1マーカーレベルを決定し、該対象からのサンプルがPin1マーカーレベルの上昇を有すると決定された場合に、表1の化合物の治療的有効量を該対象に投与する工程を含む、対象における増殖性障害の治療方法。
[9] 抗炎症化合物、抗微生物化合物、抗ウイルス化合物または抗癌化合物である第2治療用化合物の投与を更に含む、前記のいずれか1項記載の方法。
[10] 該Pin1マーカーがPin1のSer71リン酸化の低下である、7〜9のいずれか1項記載の方法。
[11] 表1の化合物の投与の後で該サンプルにおけるPin1マーカーレベルを決定することを更に含む、7〜9のいずれか1項記載の方法。
[12] 該サンプルが、血液、尿、組織生検、リンパ液、唾液、粘液、脳脊髄液および膿からなる群から選択される、7〜9のいずれか1項記載の方法。
[13] 該サンプルが罹患組織に由来する、7〜12のいずれか1項記載の方法。
[14] 該罹患組織が、腫瘍生検または分画血液からなる群から選択される、13記載の方法。
[15] Pin1マーカーレベルの上昇が遺伝性形質または体細胞突然変異によるものである、6〜14のいずれか1項記載の方法。
[16] 第2治療用化合物が、コルチコステロイド、NSAID、COX-2インヒビター、生物製剤、小分子免疫調節物質、非ステロイドイムノフィリン依存性免疫抑制物質、5-アミノサリチル酸、DMARD、ヒドロキシクロロキン硫酸塩およびペニシラミンからなる群から選択される、9記載の方法。
[17] 第2治療用化合物が、微小管インヒビター、トポイソメラーゼインヒビター、プラチン、アルキル化剤および代謝拮抗物質からなる群から選択される、9記載の方法。
[18] 第2治療用化合物が、1-D-リボフラノシル-1,2,4-トリアゾール-3-カルボキサミド、9->2-ヒドロキシ-エトキシメチルグアニン、アダマンタンアミン、5-ヨード-2'-デオキシウリジン、トリフルオロチミジン、インターフェロン、アデニンアラビノシド、プロテアーゼインヒビター、チミジンキナーゼインヒビター、糖または糖タンパク質合成インヒビター、構造タンパク質合成インヒビター、付着および吸着インヒビター、ならびにヌクレオシド類似体、例えばアシクロビル、ペンシクロビル、バラシクロビルおよびガンシクロビルからなる群から選択される、9記載の方法。
[19] 第2治療用化合物が、MK-2206、ON 013105、RTA 402、BI 2536、ソラフェニブ、ISIS-STAT3Rx、微小管インヒビター、トポイソメラーゼインヒビター、プラチン、アルキル化剤、代謝拮抗物質、パクリタキセル、ゲムシタビン、ドキソルビシン、ビンブラスチン、エトポシド、5-フルオロウラシル、カルボプラチン、アルトレタミン、アミノグルテチミド、アムサクリン、アナストロゾール、アザシチジン、ブレオマイシン、ブスルファン、カルムスチン、クロラムブシル、2-クロロデオキシアデノシン、シスプラチン、コルヒチン、シクロホスファミド、シタラビン、サイトキサン、ダカルバジン、ダクチノマイシン、ダウノルビシン、ドセタキセル、リン酸エストラムスチン、フロクスウリジン、フルダラビン、ゲンツズマブ、ヘキサメチルメラミン、ヒドロキシウレア、イホスファミド、イマチニブ、インターフェロン、イリノテカン、ロムスチン、メクロレタミン、メルファレン、6-メルカプトプリン、メトトレキサート、マイトマイシン、ミトタン、ミトキサントロン、ペントスタチン、プロカルバジン、リツキシマブ、ストレプトゾシン、タモキシフェン、テモゾロミド、テニポシド、6-チオグアニン、トポテカン、トラスツズマブ、ビンクリスチン、ビンデシンおよび/またはビノレルビンからなる群から選択される、9記載の方法。
[20] 第2治療用化合物を低用量で投与する、9記載の方法。
[21] 該免疫障害が、尋常性ざ瘡、急性呼吸窮迫症候群、アジソン病、副腎皮質機能不全、副腎性器症候群、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性眼内炎症性疾患、ANCA関連小血管血管炎、血管性浮腫、強直性脊椎炎、アフタ性口内炎、関節炎、喘息、アテローム性動脈硬化症、アトピー性皮膚炎、自己免疫疾患、自己免疫性溶血性貧血、自己免疫性肝炎、ベーチェット病、ベル麻痺、ベリリウム症、気管支喘息、水疱性疱疹状皮膚炎、水疱性類天疱瘡、心臓炎、セリアック病、脳虚血、慢性閉塞性肺疾患、肝硬変、コーガン症候群、接触性皮膚炎、COPD、クローン病、クッシング症候群、皮膚筋炎、糖尿病、円板状エリテマトーデス、好酸球性筋膜炎、上顆炎、結節性紅斑、剥脱性皮膚炎、線維筋痛症、巣状糸球体硬化症、巨細胞性動脈炎、痛風、痛風性関節炎、移植片対宿主病、手湿疹、ヘノッホ・シェーンライン紫斑病、妊娠ヘルペス、多毛症、過敏性薬物反応、特発性角膜強膜炎、特発性肺線維症、特発性血小板減少性紫斑病、炎症性腸または胃腸障害、炎症性皮膚疾患、若年性関節リウマチ、喉頭浮腫、扁平苔癬、レフラー症候群、ループス腎炎、尋常性狼瘡、リンパ腫気管気管支炎、黄斑浮腫、多発性硬化症、筋骨格および結合組織障害、重症筋無力症、筋炎、閉塞性肺疾患、眼炎症、臓器移植拒絶、骨関節炎、膵炎、妊娠性類天疱瘡、尋常性天疱瘡、結節性多発動脈炎、リウマチ性多発筋痛、一次性副腎皮質不全、原発性胆汁性肝硬変、陰嚢痒み、痒み/炎症、乾癬、乾癬性関節炎、ライター病、再発性多発性軟骨炎、リウマチ性心臓炎、リウマチ熱、関節リウマチ、サルコイドーシスにより引き起こされる酒さ、強皮症により引き起こされる酒さ、スイート症候群により引き起こされる酒さ、全身性エリテマトーデスにより引き起こされる酒さ、蕁麻疹により引き起こされる酒さ、帯状疱疹関連疼痛により引き起こされる酒さ、サルコイドーシス、強皮症、分節性糸球体硬化症、敗血症性ショック症候群、血清病、肩腱炎または滑液包炎、シェーグレン症候群、スティル病、脳卒中誘発性脳細胞死、スウィート病、全身皮膚筋炎、全身性エリテマトーデス、全身性硬化症、高安動脈炎、側頭動脈炎、甲状腺炎、中毒性表皮壊死症、結核、1型糖尿病、潰瘍性大腸炎、ブドウ膜炎、血管炎およびウェゲナー肉芽腫症からなる群から選択される、4または7記載の方法。
[22] 該増殖性障害が、急性白血病、急性リンパ性白血病、急性骨髄性白血病、急性骨髄芽球性白血病、急性前骨髄球性白血病、急性骨髄単球性白血病、急性単球性白血病、急性赤白血病、慢性白血病、慢性骨髄性白血病、慢性リンパ性白血病、ホジキン病、非ホジキン病、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、滑膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、結腸癌、膵臓癌、乳癌、卵巣癌、前立腺癌、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭状癌、乳頭状腺癌、嚢胞腺癌、髄様癌、気管支癌、腎細胞癌、肝癌、胆管癌、絨毛癌、セミノーマ、胎生期癌、ウィルムス腫瘍、子宮頸癌、子宮癌、精巣癌、肺癌、小細胞肺癌、膀胱癌、上皮癌、神経膠腫、星状細胞腫、髄芽腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽細胞腫、聴神経腫、乏突起神経膠腫、神経鞘腫、髄膜腫、黒色腫、神経芽細胞腫および網膜芽細胞腫からなる群から選択される、5または8記載の方法。
[23] 表1の化合物を含む医薬組成物。
[24] 該化合物が丸剤、軟膏剤、クリーム剤、泡剤、カプセル剤または液体として製剤化されている、23記載の医薬組成物。
Claims (20)
- 細胞内に存在するPin1を阻害するための、請求項1に記載の組成物。
- 該細胞がヒト細胞である、請求項2に記載の組成物。
- 抗炎症化合物、抗微生物化合物、抗ウイルス化合物または抗癌化合物である第2治療用化合物との併用療法用の、請求項1〜5のいずれか1項に記載の組成物。
- 該Pin1マーカーがPin1のSer71リン酸化の低下である、請求項4または5に記載の組成物。
- 前記Pin1マーカーレベルの上昇が、前記化合物を含む前記組成物の投与後の前記対象由来サンプルについて決定される、請求項4〜6のいずれか1項に記載の組成物。
- Pin1マーカーレベルを決定するための対象由来サンプルが、血液、尿、組織生検、リンパ液、唾液、粘液、脳脊髄液および膿からなる群から選択されるサンプルである、請求項8に記載の組成物。
- 対象由来サンプルが罹患組織に由来するサンプルである、請求項8又は9に記載の組成物。
- 該罹患組織が、腫瘍生検または分画血液からなる群から選択される、請求項10に記載の組成物。
- Pin1マーカーレベルの上昇が遺伝性形質または体細胞突然変異によるものである、請求項4〜11のいずれか1項に記載の組成物。
- 第2治療用化合物が、コルチコステロイド、NSAID、COX-2インヒビター、生物製剤、小分子免疫調節物質、非ステロイドイムノフィリン依存性免疫抑制物質、5-アミノサリチル酸、DMARD、ヒドロキシクロロキン硫酸塩およびペニシラミンからなる群から選択される、請求項6に記載の組成物。
- 第2治療用化合物が、微小管インヒビター、トポイソメラーゼインヒビター、プラチン、アルキル化剤および代謝拮抗物質からなる群から選択される、請求項6に記載の組成物。
- 第2治療用化合物が、1-D-リボフラノシル-1,2,4-トリアゾール-3-カルボキサミド、9->2-ヒドロキシ-エトキシメチルグアニン、アダマンタンアミン、5-ヨード-2'-デオキシウリジン、トリフルオロチミジン、インターフェロン、アデニンアラビノシド、プロテアーゼインヒビター、チミジンキナーゼインヒビター、糖または糖タンパク質合成インヒビター、構造タンパク質合成インヒビター、付着および吸着インヒビター、ならびにヌクレオシド類似体、アシクロビル、ペンシクロビル、バラシクロビルおよびガンシクロビルからなる群から選択される、請求項6に記載の組成物。
- 第2治療用化合物が、MK-2206、ON 013105、RTA 402、BI 2536、ソラフェニブ、ISIS-STAT3Rx、微小管インヒビター、トポイソメラーゼインヒビター、プラチン、アルキル化剤、代謝拮抗物質、パクリタキセル、ゲムシタビン、ドキソルビシン、ビンブラスチン、エトポシド、5-フルオロウラシル、カルボプラチン、アルトレタミン、アミノグルテチミド、アムサクリン、アナストロゾール、アザシチジン、ブレオマイシン、ブスルファン、カルムスチン、クロラムブシル、2-クロロデオキシアデノシン、シスプラチン、コルヒチン、シクロホスファミド、シタラビン、サイトキサン、ダカルバジン、ダクチノマイシン、ダウノルビシン、ドセタキセル、リン酸エストラムスチン、フロクスウリジン、フルダラビン、ゲンツズマブ、ヘキサメチルメラミン、ヒドロキシウレア、イホスファミド、イマチニブ、インターフェロン、イリノテカン、ロムスチン、メクロレタミン、メルファレン、6-メルカプトプリン、メトトレキサート、マイトマイシン、ミトタン、ミトキサントロン、ペントスタチン、プロカルバジン、リツキシマブ、ストレプトゾシン、タモキシフェン、テモゾロミド、テニポシド、6-チオグアニン、トポテカン、トラスツズマブ、ビンクリスチン、ビンデシンおよび/またはビノレルビンからなる群から選択される、請求項6に記載の組成物。
- 第2治療用化合物が低用量で投与されるためのものである、請求項6に記載の組成物。
- 該免疫障害が、喘息、自己免疫疾患、慢性閉塞性肺疾患、皮膚筋炎、糖尿病、多発性硬化症、臓器移植拒絶、乾癬、関節リウマチ、シェーグレン症候群、全身性エリテマトーデス、及び甲状腺炎からなる群から選択される、請求項4に記載の組成物。
- 該増殖性障害が、急性白血病、急性リンパ性白血病、急性骨髄性白血病、急性骨髄芽球性白血病、急性前骨髄球性白血病、急性骨髄単球性白血病、急性単球性白血病、急性赤白血病、慢性白血病、慢性骨髄性白血病、慢性リンパ性白血病、ホジキン病、非ホジキン病、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、滑膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、結腸癌、膵臓癌、乳癌、卵巣癌、前立腺癌、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭状癌、乳頭状腺癌、嚢胞腺癌、髄様癌、気管支癌、腎細胞癌、肝癌、胆管癌、絨毛癌、セミノーマ、胎生期癌、ウィルムス腫瘍、子宮頸癌、子宮癌、精巣癌、肺癌、小細胞肺癌、膀胱癌、上皮癌、神経膠腫、星状細胞腫、髄芽腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽細胞腫、聴神経腫、乏突起神経膠腫、神経鞘腫、髄膜腫、黒色腫、神経芽細胞腫および網膜芽細胞腫からなる群から選択される、請求項5に記載の組成物。
- 該組成物が丸剤、軟膏剤、クリーム剤、泡剤、カプセル剤または液体として製剤化されている、請求項1〜19のいずれか1項に記載の組成物。
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US11129835B2 (en) | 2021-09-28 |
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EP2858648A4 (en) | 2015-12-30 |
US10413548B2 (en) | 2019-09-17 |
US20200093832A1 (en) | 2020-03-26 |
CA2875798A1 (en) | 2013-12-12 |
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US20170304310A1 (en) | 2017-10-26 |
EP2858648B1 (en) | 2018-08-22 |
US9730941B2 (en) | 2017-08-15 |
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EP2858648A1 (en) | 2015-04-15 |
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