JP7421499B2 - 腫瘍転移および腫瘍発生の予防および治療のための製剤および方法 - Google Patents
腫瘍転移および腫瘍発生の予防および治療のための製剤および方法 Download PDFInfo
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Description
本出願は、2018年5月15日に提出された米国仮特許出願No.62/671,964の利益を主張するものであり、参照することによりその全体が本明細書に組み込まれる。
本発明は、国立衛生研究所国立がん研究所のプロジェクト番号1ZIABC011267-08の下で政府の支援を受けて行われた。政府は本発明について一定の権利を有している。
本明細書には、参照によりその全体が組み込まれており、同時に提出され、以下のように識別されるコンピュータ読み取り可能なヌクレオチド/アミノ酸配列リストが記載されている:2019年5月13日付けで「743502_ST25.txt」と名付けられた1つの12,619バイトのASCII(テキスト)ファイル。
転移とは、疾患が臓器から生体の別の隣接しない部分に広がるために用いられる細胞のメカニズムである。この過程は固形腫瘍の発生に関与している可能性があり、疾患に関連した死亡の大部分の原因である可能性がある。腫瘍性病変の治療は、転移前の段階で開始すると予後が良好になることがある。過去10年間で、転移に関与する基礎的なメカニズムの理解は進んできたが、特に転移過程に影響を与える治療上のツールは非常に限られている。そのため、転移性疾患を患っている対象者を治療するための新しい製剤や方法が必要とされている。
本発明の一実施形態として、式(I):
製剤
発明の実施形態として、式(I):
R2が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R3が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、および
R4が、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、またはヘテロアリールアルキルであって、
R1およびR4は、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、アミノスルホニル、ヒドロキシル、パーフルオロアルコキシ、アルキレンジオキシ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基でアリールおよび/またはアルキル部分で置換されてもよい)の化合物またはその医薬上許容し得る塩を含む製剤を提供する。
本発明の一実施形態としては、哺乳動物の膵臓腺がんを治療する方法を提供し、該方法はそれを必要とする哺乳動物に式(I):
投与される化合物の治療有効量は、所望の効果および上述の要因に応じて変化し得る。一つの実施形態では、投与量は、対象者の体重の0.1mg/kgから80mg/kgの間である。一つの実施形態では、投与量は、対象者の体重の0.1mg/kgから70mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから60mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから50mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから40mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから30mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから20mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから10mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから9mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから8mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから7mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから6mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから5mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから4mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから3mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから2mg/kgの間である。一つの実施形態において、投与量は、対象者の体重の0.1mg/kgから1mg/kgの間である。
本明細書の方法は、式(I)の化合物の有効量を、膵臓腺がんに罹患している動物に投与することを含む。好ましくは、動物は哺乳動物である。より好ましくは、哺乳動物はヒトである。
本発明の一つの実施形態は、哺乳動物からの膵臓腺がん腫瘍サンプル中のFoxA1およびFoxO6の一方または両方の発現レベルの変化を検出する方法を提供する。ここで、哺乳動物は式(I)の化合物を投与されている。該方法は、哺乳動物から第1の膵臓腺がん腫瘍サンプルを提供する工程、腫瘍サンプルをアッセイして、FoxA1およびFoxO6の一方または両方の発現レベルを決定する工程、哺乳動物から第2の膵臓腺がん腫瘍サンプルを提供する工程、第2の腫瘍サンプルをアッセイして、FoxA1およびFoxO6の一方または両方の発現レベルを決定する工程、および(i)FoxA1の第2の決定された発現レベルに対するFoxA1の第1の決定された発現レベルおよび(ii)FoxO6の第1の決定された発現レベルとFoxO6の第2の決定された発現レベルとを比較、の一方または両方を比較して、FoxA1およびFoxO6の一方または両方の発現レベルの変化を検出する工程を含み、ここで哺乳動物から第2の腫瘍サンプルを摘出する前に、第1の腫瘍サンプルが哺乳動物から摘出される。
今般、本明細書で一般的に使用される専門用語を参照すると、用語「アルキル」は、例えば、約1から約6個の炭素原子、好ましくは約1から約4個の炭素原子、より好ましくは約1から約2個の炭素原子を含む直鎖または分枝状のアルキル置換基を意味する。かかる置換基としては、メチル、エチル、プロピル、イソプロピル、n-ブチル、sec-ブチル、イソブチル、tert-ブチル、ペンチル、イソアミル、ヘキシル等が挙げられる。
(1) 以下を含む医薬製剤:
(a) 式(I):
R2が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル
R3が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R4が、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、およびヘテロアリールアルキルからなる群より選ばれ、
R1およびR4は、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、アミノスルホニル、ヒドロキシル、パーフルオロアルコキシ、アルキレンジオキシ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基でアリールおよび/またはアルキル部分で置換されてもよい)の化合物またはその医薬上許容し得る塩;および
(b) 1つ以上のカプリロカプロイルポリオキシルグリセリドおよびPEG-8カプリリック/カプリックグリセリドを含む医薬上許容し得る界面活性剤。
(a)式(I):
R2が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R3が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R4が、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、およびヘテロアリールアルキルからなる群より選ばれ、
R1およびR4は、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、アミノスルホニル、ヒドロキシル、パーフルオロアルコキシ、アルキレンジオキシ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基でアリールおよび/またはアルキル部分で置換されてもよい)の化合物またはその医薬上許容し得る塩;および
(b) 1つ以上の12-ヒドロキシステアリン酸のポリオキシエチレンエステルを含む医薬上許容し得る界面活性剤。
R2が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R3が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R4が、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、およびヘテロアリールアルキルからなる群より選ばれ、
R1およびR4は、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、アミノスルホニル、ヒドロキシル、パーフルオロアルコキシ、アルキレンジオキシ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基でアリールおよび/またはアルキル部分で置換されてもよい)の化合物またはその医薬上許容し得る塩を投与する工程を含む方法。
(I)哺乳動物の細胞内の核周囲コンパートメントを破壊すること、
(II)哺乳動物の細胞内の核周囲コンパートメントの有病率を低下させること、
(III)哺乳動物の転移性がん細胞が産生するアデノシン三リン酸(ATP)レベルを低下させること、
(IV)哺乳動物のがん細胞のコロニー形成を減少させること、および
(V)哺乳動物のがん細胞の遊走を減少させること。
R2が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R3が、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基で置換されてもよいフェニル、
R4が、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、およびヘテロアリールアルキルからなる群より選ばれ、
R1およびR4は、ハロ、アルキル、ヒドロキシアルキル、チオアルキル、アルコキシ、アルキルチオアルキル、アルコキシカルボニル、アルキルチオカルボニル、アミノ、アルキルアミノ、ジアルキルアミノ、アミノスルホニル、ヒドロキシル、パーフルオロアルコキシ、アルキレンジオキシ、およびアルキルカルボニルからなる群より選ばれる1つ以上の置換基でアリールおよび/またはアルキル部分で置換されてもよい)の化合物またはその医薬上許容し得る塩を投与されており、以下の工程を含む方法:
(a)哺乳動物から第1の膵臓腺がん腫瘍サンプルを提供する工程、
(b)腫瘍サンプルをアッセイして、フォークヘッドボックスタンパク質A1(FoxA1)およびフォークヘッドボックスタンパク質O6(FoxO6)の一方または両方の発現レベルを決定する工程、
(c)哺乳動物から第2の膵臓腺がん腫瘍サンプルを提供する工程、
(d)第2の腫瘍サンプルをアッセイして、FoxA1およびFoxO6の一方または両方の発現レベルを決定する工程;および
(e)(i)第2の決定された発現レベルに対するFoxA1の第1の決定された発現レベル、および(ii)FoxO6の第1の決定された発現レベルとFoxO6の第2の決定された発現レベルとを比較、の一方または両方を比較して、FoxA1およびFoxO6の一方または両方の発現レベルの変化を検出する工程、
ここで哺乳動物から第2の腫瘍サンプルを摘出する前に、第1の腫瘍サンプルが哺乳動物から摘出される。
a)FoxA1およびFoxO6の一方または両方の発現レベルの変化の決定を受ける工程であって、変化が、(i)FoxA1発現の第2の決定されたレベルがFoxA1発現の第1の決定されたレベルよりも低いこと、および(ii)FoxO6発現の第2の決定されたレベルがFoxO6発現の第1の決定されたレベルよりも高いこと、のうちの一方または両方であり、FoxA1およびFoxO6の一方または両方の発現レベルの変化が、実施形態41に記載の方法によって決定される;
b)式(I)の化合物の投与に対する臨床応答を予測する工程;ならびに
c)変化が、(i)FoxA1発現の第2の決定されたレベルがFoxA1発現の第1の決定されたレベルよりも低い、および(ii)FoxO6発現の第2の決定されたレベルがFoxO6発現の第1の決定されたレベルよりも高い、のいずれか一方または両方である場合に、式(I)の化合物を哺乳動物に投与することにより哺乳動物の膵臓線がんを治療する工程。
本実施例では、式(I)の化合物を、転移性挙動の表現型マーカーおよびサロゲートとしてPNCを用いて同定した方法を説明する。
本実施例は、式(I)の化合物であるメタレスチンが、がん細胞型におけるPNCを破壊することを示している。
本実施例は、式(I)の化合物であるメタレスチンが、ヒト膵臓がん異種移植のマウスモデルにおいて転移を抑制し、生存期間を延長することを示す。
実施例は、式(I)の化合物、メタレスチンが、好ましいPKプロファイルを有し、メタレスチンの投与が、メタレスチンで処置したマウスの転移-関連死をうまく抑制していることを示している。
この実施例は、メタレスチン処理が、核小体構造を破壊し、Pol I転写を阻害することを示す。
この実施例は、メタレスチン処理がrDNAプロモーターにおけるプレRNA合成およびPol I占有を減少させることを実証する。
本実施例は、RPA194の減少がメタレスチンによる核小体とPNCの破壊を部分的にフェノコピーすることを示す。
本実施例は、メタレスチンが翻訳伸長因子eEFIAを結合することを示している。
Claims (16)
- 以下を含むがん治療用医薬製剤:
(a)式(I):
(式中、R1が、
からなる群より選ばれ、
R2が、フェニル、
R3が、フェニル、
R4が、ベンジルである)
の化合物またはその医薬上許容し得る塩;
(b)1つ以上のカプリロカプロイルポリオキシルグリセリドおよびPEG-8カプリリック/カプリックグリセリドを含む医薬上許容し得る界面活性剤;ならびに
(c)カプリル酸。 - 式(I)の化合物がメタレスチンである、請求項1に記載の製剤。
- ヒトの膵臓腺がん治療用である、請求項1又は2に記載の製剤。
- ヒトへの製剤の投与が(I)-(V)の1つ以上の結果になる、請求項1~3のいずれか1項に記載の製剤:
(I)ヒトの細胞内の核周囲コンパートメントを破壊すること、
(II)ヒトの細胞内の核周囲コンパートメントの有病率を低下させること、
(III)ヒトの転移性がん細胞が産生するアデノシン三リン酸(ATP)レベルを低下させること、
(IV)ヒトのがん細胞のコロニー形成を減少させること、および
(V)ヒトのがん細胞の遊走を減少させること。 - ヒトがステージI膵臓腺がん、ステージII膵臓腺がん、ステージIII膵臓腺がんおよびステージIV膵臓腺がんからなる群から選択されるステージの膵臓腺がんを有する、請求項1~4のいずれか1項に記載の製剤。
- ヒトが転移性膵臓腺がんを有する、請求項1~4のいずれか1項に記載の製剤。
- ヒトへの式(I)の化合物の投与が、確立された転移巣のさらなる転移を減少または遅延させる、請求項1~6のいずれか1項に記載の製剤。
- 1つ以上の膵臓腺がん腫瘍が手術によってヒトから摘出されている、請求項1~7のいずれか1項に記載の製剤。
- ヒトへの式(I)の化合物の投与が、転移巣の量または大きさを減少させる、請求項1~8のいずれか1項に記載の製剤。
- ヒトへの式(I)の化合物の投与が、転移巣の成長を減少または遅延させる、請求項1~9のいずれか1項に記載の製剤。
- 式(I)の化合物0.1から80mg/kgをヒトに投与する、請求項1~10のいずれか1項に記載の製剤。
- (i)請求項1~11のいずれか1項に記載の製剤および(ii)化学療法剤または放射線処置の組み合わせを含む、ヒトの膵臓腺がん治療用組み合わせ医薬。
- 化学療法剤を含む、請求項12に記載の医薬。
- 化学療法剤がゲムシタビンである、請求項13に記載の医薬。
- 化学療法剤が、式(I)の化合物と任意の順序で連続投与される、請求項12~14のいずれか1項に記載の医薬。
- 化学療法剤が、式(I)の化合物と同時に投与される、請求項12~14のいずれか1項に記載の医薬。
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