JP2021511342A - 癌処置のためのbcl−2タンパク質分解剤 - Google Patents
癌処置のためのbcl−2タンパク質分解剤 Download PDFInfo
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Abstract
Description
本発明はアメリカ国立衛生研究所により与えられたCA219836およびCA223371のもと、政府の支援により完成した。政府は、本発明において特定の権利を有する。
本出願は2018年1月22日に出願された米国仮出願番号第62/620,219号の利益を主張するものであり、その開示は全体の参照により本明細書に包含させる。
本発明は、Bcl−2ファミリータンパク質の分解を誘発する組成物および多様な癌の処置におけるそれらの使用方法に関する。
本発明の化合物は、抗アポトーシスBcl−2ファミリーのタンパク質の分解を促進することができる二価化合物である。これらの二価化合物はBcl−2小分子阻害剤またはリガンドをE3リガーゼ結合部分、例えば、フォンヒッペル・リンドウ(VHL)E3リガーゼ結合部分(例えば、VHLE3リガーゼリガンドを含むHIF−1α−由来の(R)−ヒドロキシプロリン)またはセレブロン(CRBN)E3リガーゼ結合部分(ポマリドミドのようなサリドマイド誘導体)に結合させる。VHLは、転写因子HIF−1αの分解に重要である、cullin−2(CUL2)を含むE3ユビキチンリガーゼ複合体エロンギンBC−CUL2−VHL(CRL2VHLとして知られる)の一部である。HIF−1α由来の(R)−ヒドロキシプロリンを含むVHLE3リガーゼリガンドが高い親和性とともに特定された。CRBNは、cullin−4(CUL4)を含むE3ユビキチンリガーゼ複合体CUL4−RBX1−DDB1−CRBN(CRL4CRBNとして知られる)の一部である。サリドマイドおよびその誘導体、例えばレナリドマイドおよびポマリドミドは、CRBN複合体と特異的に相互作用し、不可欠なIKAROS転写因子の分解を誘発する。サリドマイドの非フタルイミドアナログであるCC−122もまた、CRBN E3リガーゼ複合体と相互作用するが、リンパ系転写因子Aiolosの分解を誘発する。二価化合物はCRBNまたはVHL E3リガーゼのようなE3ユビキチンリガーゼに抗アポトーシスBcl−2ファミリーのタンパク質を能動的に動員し、ユビキチンプロテアソーム系によるそれらの分解をもたらし得る。
ある態様において、本発明の組成物は式(I)の化合物を含む。非修飾化合物と比較して効能、選択性、バイオアベイラビリティ、溶解度、安定性、処理特性またはそれらの組合せを改善するために、式(I)の誘導体が製造され得る。
式(I):
R1はハロゲン、CH3、CF3であり;
R2、R3、R4およびR5は独立して、H、F、CH3、CHF2、CF3、CH2F、CH2OH、CH2OCH3またはCH3Oから選択され;
R6はC1−4アルキルスルホニル、C1−4ハロアルキルスルホニル、ハロゲン、NO2またはCNであり;
XはOまたはNHであり;
nは0〜3の整数であり;
R7はH、C1−4アルキルまたはC1−4アルコールであり;
Yは存在しないか、−O−、−N(R7)−、
ここで、R7はH、C1−4アルキルまたはC1−4アルコールであり;
Zは存在しないか、−CH2−、−O−、−N(R8)−、−C(=O)N(R8)−、−N(R8)C(=O)(CH2)0−3O−または−N(R8)C(=O)(CH2)0−3N(R9)−であり;
ここで、R8およびR9は独立して、HまたはC1−4アルキルであり;
−C(=O)N(R8)−の炭素原子はLに結合し;
−N(R8)C(=O)(CH2)0−3O−および−N(R8)C(=O)(CH2)0−3N(R9)−の窒素原子はLに結合し;
Lはアルキル、分岐アルキル、エーテル、チオエーテル、エステル、アミン、アミド、カルバメート、カルボアミド、スルホン、アリール、ヘテロアリール、カルボニル、シクロアルキルまたはヘテロ環式基によりYおよびZと共有結合的に結合させるリンカー単位であり、その両端は同一でも異なってもよく;前記リンカー単位はアルキル、分岐アルキル、エーテル、チオエーテル、エステル、アミン、アミド、カルバメート、カルボアミド、スルホン、アリール、ヘテロアリール、カルボニル、シクロアルキルおよびヘテロ環式基の中の2以上の基の組合せを含み得て;前記リンカー単位は最も短い鎖長で1〜30原子の鎖長を含み;そして
AはE3ユビキチンリガーゼに結合するE3ユビキチンリガーゼ結合単位であり、非限定的な例において、Aは
ここで、R10はH、D、CH3またはFである〕
を含む化合物が、ここに提供される。
から選択される、前記式(I)の化合物のいずれかを含む。別の好ましい実施態様において、式(I)の化合物は、Yが
である、前記式(I)の化合物のいずれかを含む。別の好ましい実施態様において、式(I)の化合物は、Aが
である、前記式(I)の化合物のいずれかを含む。さらに別の好ましい実施態様において、式(I)の化合物は、Aが
本発明はまた、医薬組成物を提供する。医薬組成物は、有効成分としての式(I)の化合物および少なくとも1つの薬学的に許容される賦形剤を含む。
ミセルは、水中の油滴状であり、逆ミセルは、油中の水滴状である。別の実施形態において、マイクロエマルジョン構造はラメラである。これは界面活性剤の層で分離された水と油の連続的な層を含む。マイクロエマルジョンの「油」は、好ましくはリン脂質を含む。リポソームのための任意の上記リン脂質は、マイクロエマルジョンに関する実施形態に適切である。式(I)を含む化合物は、当分野で一般に知られる任意の方法によりマイクロエマルジョンに封入され得る。
ある態様において、組成物は少なくとも1以上の抗癌治療剤をさらに含む。
本発明はまた、対象における1以上の癌を死滅させる方法を包含する。方法は、処置を必要とする対象に治療有効量の本発明の化合物を投与することを含む。
組成物および方法において有用な化合物は、本明細書に記載のものの任意の医薬的に許容される形態が含まれ、これらとしては、ジアステレオマーおよびエナンチオマーのような異性体、塩、溶媒和物および多形体ならびに、適切な場合には、本明細書に記載の化合物のラセミ混合物および純粋な異性体を含む本明細書に記載の化合物の薬学的に許容されるいずれかの形態の化合物を含む。
急性リンパ芽球性白血病(MOLT4およびRS4;11)、小細胞肺癌(NCI−H146または単にH146)および多発性骨髄腫(EJMおよびH929)を含む種々の組織起源に由来する癌細胞を、濃度を増加させた化合物番号55またはABT−263と72時間インキュベートした。細胞生存率をテトラゾリウムベースMTSアッセイにより測定し、IC50をビークル処置した細胞の割合として計算した。
MOLT4細胞およびヒト血小板を濃度を増加させた化合物番号55で16時間処理した。細胞を収集し、プロテアーゼおよびホスファターゼ阻害剤カクテルを添加したRIPA溶解緩衝液中で溶解した。等量のタンパク質(20μg/レーン)をプレキャスト4〜20% SDS−PAGEゲル上で溶解した。タンパク質をその後電気泳動によりNOVEX PVDF膜に移動させた。膜をブロッキング緩衝液(脱脂粉乳の5% TBS−T溶液)中でブロックし、一次抗体と(最適化した濃度で)4℃で一晩インキュベートした。TBS−T中で3回洗浄後、膜を適切なHRP−コンジュゲート二次抗体と室温で1時間インキュベートした。3回徹底的に洗浄した後、目的のタンパク質をECLウェスタンブロッティング検出試薬で検出し、オートラジオグラフィー(Pierce Biotech、ロックフォード、イリノイ州、アメリカ合衆国)で記録した。Bcl−xL(カタログ番号2762)、Bcl−2(カタログ番号2872)、Mcl−1(カタログ番号5453)およびβ−アクチン(カタログ番号4970)に対する第一抗体をCell Signaling technologyから購入した。ImageJソフトウェアを用いて相対的なバンド強度を測定し、β−アクチンに対して正規化した。GraphPad Prismを用いてDC50(50%分解濃度)を計算した。化合物番号55は用量依存的にMOLT4細胞におけるBcl−xLの分解を誘発し、DC50およびDmax(最大分解)はそれぞれ0.063μMおよび90.8%であった。Bcl−2レベルは検出されず、一方でMcl−1はMOLT4細胞における化合物番号55処理に影響を与えなかった(図1Bおよび1D)。化合物番号55はヒト血小板におけるBcl−xLレベルに影響を与えず、一方でBcl−2およびMcl−1は検出されなかった(図1C)。血小板における化合物番号55のDC50およびDmax値はそれぞれ、>3μMおよび26%であった(図1E)。
Bcl−2ファミリータンパク質に対する化合物番号55の結合親和性を評価するために、室温でアルファLISA競争的アッセイを実施し、試薬を250mM HEPES pH 7.5、1 M NaCl、1% BSAおよび0.05% Tween−20を含む緩衝液に希釈した。精製した組み換えHisタグ化Bcl−xL/Bcl−2/Bcl−w(Sigma−Aldrich、セントルイス、ミズーリ州)を最終体積40μLの濃度を増加させた化合物番号55および固定された濃度のビオチンタグ化Bad(Bcl−xLについて)またはBIMペプチド(Bcl−2およびBcl−wについて)(AnaSpec、Fremont、カリフォルニア州)と96ウェルPCRプレート中でインキュベートした。24時間インキュベート後、5μLの6×His−アクセプタービーズ(最終濃度20μg/mL)(PerkinElmer、ヒューストン、テキサス州)を各ウェルに添加し、1時間インキュベートした。その後、5μLのストレプトアビジン供与体ビーズ(最終濃度20μg/mL)(PerkinElmer)を各ウェルに添加し、0.5時間インキュベートした。インキュベート期間終了時、17μLの各サンプルを384ウェルプロキシプレートの隣接するウェルに移した。Biotek’s Synergy Neo2マルチモードプレートリーダーでアルファプログラムを用いてプレートをスキャンした。各タンパク質/ペプチド対について実験的に決定したKdに基づいて、GraphPad Prismで非線形回帰、1部位、競争的結合、Fit Ki関数を用いて阻害定数(Ki)を計算した。
腫瘍細胞を固定された濃度の化合物番号55で16時間(RS4;11、EJM、H929)または48時間(H146)インキュベートし、上記のとおりウェスタンブロット分析を用いてBcl−2/Bcl−xL/Mcl−1レベルを決定した。
MOLT4細胞を、固定された濃度の化合物番号55と時点を増やしてインキュベートした。別の実験では、細胞を16時間処理した後、薬を除き、さらに培養して時点を増やした後、Bcl−xL分解アッセイのために回収した。上記のとおりウェスタンブロット分析を用いてBcl−xLレベルを測定した。ImageJソフトウェアを用いて相対的なバンド強度を測定し、等量の充填対照β−アクチンに対して正規化した。
まず、Bcl−xL分解およびより有効な細胞殺滅のためにVHL−リガンド(VHL−L)とBcl−xLリガンド(ABT263)の間にリンカーが必要であることを確認しようとした。MOLT4細胞は1μMのABT−263または10μMのVHL−Lまたは両方の組合せ剤と16時間インキュベートし、Bcl−xL発現についてウェスタンブロット分析を実施した。MOLT4細胞を1μMおよび2μMのVHL−Lを伴うまたは伴なわない濃度を増加させたABT263で72時間処理し、MTSアッセイを用いて細胞生存率を測定した。
MOLT4細胞を0.1および0.3μMの化合物番号55またはABT−263と24時間インキュベートした。インキュベートの終了時、開裂および全長カスパーゼ−3ならびにポリ(ADP)リボースポリメラーゼ(PARP)のウェスタンブロット分析のために細胞を収集した。開裂カスパーゼ−3(カタログ番号9661)、全長カスパーゼ−3(カタログ番号9662)およびPARP(カタログ番号9532)に対する抗体をCell Signaling Technologyから購入した。使用した一個の抗PARP抗体で、開裂および全長PARPの両方を検出できる。
小細胞肺癌H146細胞を500nMのABT−199(Bcl−2阻害剤)または125nMの化合物番号55のいずれかまたは両化合物の組合せ剤で72時間インキュベートした。MTSアッセイを用いて細胞生存率を測定した。式CI=AB/(A×B)を用いて併用係数(CI)を計算し、式中、ABは組合せ剤によるパーセント細胞阻害であり、AおよびBは個々の薬剤によるパーセント細胞阻害である。CI<1は相乗効果を示し、CI<0.3は強い相乗効果を示す。
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Claims (25)
- R1がハロゲン、CH3またはCF3である、請求項1または2に記載の化合物。
- R2、R3、R4およびR5がHであるか、独立してF、CH3またはCH3Oである、請求項3に記載の化合物。
- R2がF、CH3またはCH3Oである、請求項3に記載の化合物。
- R3がF、CH3またはCH3Oである、請求項3に記載の化合物。
- R4がF、CH3またはCH3Oである、請求項3に記載の化合物。
- R5がF、CH3またはCH3Oである、請求項3に記載の化合物。
- XがOまたはNHである、請求項2に記載の化合物。
- Zが存在しないか、−CH2−、−O−、−N(R8)−、−C(=O)N(R8)−、−N(R8)C(=O)(CH2)0−3O−または−N(R8)C(=O)(CH2)0−3N(R9)−であり;R8およびR9が独立して、HまたはC1−4アルキルである、
請求項2に記載の化合物。 - −C(=O)N(R8)−の炭素原子がLに結合する、または
−N(R8)C(=O)(CH2)0−3O−または−N(R8)C(=O)(CH2)0−3N(R9)−の窒素原子がLに結合する、
請求項12に記載の化合物。 - Lが両端が同一または異なってよいアルキル、分岐アルキル、エーテル、チオエーテル、エステル、アミン、アミド、カルバメート、カルボアミド、スルホン、アリール、ヘテロアリール、シクロアルキルまたはヘテロ環式基によりYおよびZに共有結合するリンカー単位であり;前記リンカー単位がアルキル、分岐アルキル、エーテル、チオエーテル、エステル、アミン、アミド、カルバメート、カルボアミド、スルホン、アリール、ヘテロアリール、シクロアルキルおよびヘテロ環式基の中の2以上の基の組合せを含み;リンカー単位が最も短い長さで1〜30個の原子を含む、請求項1〜13のいずれか一項に記載の化合物。
- 処置を必要とする対象に治療有効量の請求項1に記載の化合物を含む組成物を投与することを含む、前記対象における1以上の癌細胞を選択的に殺滅させる方法。
- 哺乳動物に治療有効量の請求項1に記載の化合物を投与することを含む、前記哺乳動物における癌の処置方法。
- 処置を必要とする対象に治療有効量の請求項1に記載の化合物を投与することを含む、前記対象におけるBcl−2タンパク質を分解する方法。
- 処置を必要とする対象に、Bcl−2タンパク質の分解による癌の処置に使用するための、請求項1に記載の化合物ならびに賦形剤および/または薬学的に許容される担体を含む組成物を投与する方法。
- 請求項1に記載の化合物および第二の癌治療剤を含む、組成物。
- 請求項1に記載の化合物、第二の癌治療剤および賦形剤および/または薬学的に許容される担体を含む、組成物。
- (なし)
- 第二の癌治療剤がアルキル化剤、抗代謝剤、抗腫瘍抗生物質、抗細胞骨格剤、トポイソメラーゼ阻害剤、抗ホルモン剤、標的化治療剤、光線力学治療剤またはそれらの組合せ剤から成る群から選択される、請求項20または請求項21に記載の組成物。
- 請求項20〜23のいずれか一項に記載の組成物を投与することを含む、処置を必要とする対象における癌の処置方法。
- 処置を必要とする対象に請求項1に記載の化合物を含む組成物および癌放射線療法を投与することを含む、癌の処置方法。
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