JP2015500885A - 癌を治療するためのchk1阻害剤と組み合わせた低酸素活性化プロドラッグの投与 - Google Patents
癌を治療するためのchk1阻害剤と組み合わせた低酸素活性化プロドラッグの投与 Download PDFInfo
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Abstract
Description
本発明は、癌を治療するための方法、ならびに該方法に有用な医薬製剤および単位投与形態を提供する。そのため、本発明は、医学および薬学の分野に関する。
TH-302は、癌の治療のための臨床開発における低酸素活性化プロドラッグである。PCT公報第2007/002931号、第2008/083101号、第2010/048330号、第2012/006032号、第2012/009288号、第2012/135757号、第2012/142520号および2012年1月31日に出願された米国仮特許出願第61/593,249号(該文献のそれぞれは、参照により本明細書に援用される)を参照。TH-302は、低酸素条件下で、DNA架橋ブロモ-イソホスホルアミデート(bromo-isophosphoramidate)(時々、ブロモ-イソホスホルアミド(bromo-isophosphoramide)と称される)マスタード(mustard)(Br-IPM)を放出する。TH-302は、低濃度ではG2/M停止を誘導し、高濃度では汎細胞周期(pan-cell cycle)停止を誘導する。
第1の局面において、本発明は、癌を治療する方法を提供し、前記方法は、かかる治療を必要とする患者に、治療有効量のChk1阻害剤と組み合わせた治療有効量の低酸素活性化プロドラッグを投与する工程を含む。
Y2は、O、S、NR6、NCOR6またはNSO2R6であり、
ここでR6は、C1-C6アルキル、C1-C6ヘテロアルキル、アリールまたはヘテロアリールであり;R3およびR4は独立して、2-ハロアルキル、2-アルキルスルホニルオキシアルキル、2-ヘテロアルキルスルホニルオキシアルキル、2-アリールスルホニルオキシアルキルおよび2-ヘテロアルキルスルホニルオキシアルキルからなる群より選択され;R1は、式L-Z3を有し;Lは、C(Z1)2であり;各Z1は独立して、水素、ハロゲン、C1-C6アルキル、C1-C6ヘテロアルキル、アリール、ヘテロアリール、C3-C8シクロアルキル、ヘテロシクリル、C1-C6アシル、C1-C6ヘテロアシル、アロイルもしくはヘテロアロイルであり;または
Lは:
Z3は:
ここで、各X1は独立して、NまたはCR8であり;X2は、NR7、SまたはOであり;各R7は独立して、C1-C6アルキル、C1-C6ヘテロアルキル、C3-C8シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり;R8は独立して、水素、ハロゲン、シアノ、CHF2、CF3、CO2H、アミノ、C1-C6アルキル、C1-C6ヘテロアルキル、C1-C6シクロアルキル、C1-C6アルコキシ、C1-C6アルキルアミノ、C1-C6ジアルキルアミノ、アリール、CON(R7)2、C1-C6アシル、C1-C6ヘテロアシル、アロイルまたはヘテロアロイルである)
の化合物、またはその薬学的に許容され得る塩である。本発明の種々の態様において、本発明に使用される化合物は、式Iの化合物であり、TH-281、TH-302またはTH-308である(構造を以下に示す)。
本発明の実施は、当該分野の技術の範囲内の有機化学、分子生物学(組み換え技術など)、微生物学、細胞生物学、生化学および免疫学の従来の技術の使用を含む。
以下の明細書および特許請求の範囲において、以下の意味を有する多くの用語に対する参照がなされる。全ての数値指定、例えばpH、温度、時間、濃度および重量(それらのそれぞれの範囲を含む)は、適切な場合に0.1、1.0または10.0の増分により典型的に(+)または(-)に変化し得る近似値である。全ての数値指定は、用語「約」が前につくと理解され得る。本明細書に記載される試薬は、当該技術分野で公知であり得るものの典型および同等物である。
が挙げられる。
一局面において、本発明は、癌の治療を必要とする患者に、治療有効量の式Iの低酸素活性化プロドラッグおよび治療有効量のChk1阻害剤を投与し、それにより癌を治療する工程を含む、癌の治療方法を提供する。一態様において、以前にChk1阻害剤または式Iの低酸素活性化プロドラッグで治療されたが、治療にも関わらず癌が進行しているか、または癌の進行のために治療が中断された患者に組み合わせ療法が施与される。他の態様において、患者は、任意の抗癌薬で以前に治療されていない。他の態様において、患者は、Chk1阻害剤または式Iの低酸素活性化プロドラッグ以外の抗癌薬で以前に治療されている。
575mg/m2で1週間に1回;
670 mg/m2で3週間毎に1回;
300、340または480mg/m2で、21日のサイクル中、1日目および8日目;
240または340mg/m2で、21日のサイクル中、1日目、8日目および15日目;
240〜480mg/m2で、21日のサイクル中、1日目、4日目、8日目および11日目;
460mg/m2で、21日のサイクル中、1日目〜5日目;
240〜575mg/m2で、28日のサイクル中、1日目、8日目および15日目;
240〜575mg/m2、例えば480mg/m2で、28日のサイクル中、8日目、15日目および22日目、ここで、Chk1阻害剤投与は、1日目に開始される;ならびに
240〜670mg/m2で2週間毎に1回、これは手術に続き得る、
が挙げられる。
以下の化合物は、本発明による式Iの低酸素活性化プロドラッグと組み合わせた投与に有用である。
細胞を、通常酸素または低酸素のいずれかの下、2時間、TH-302およびChk1阻害剤(0.4μM PF477736、0.1μM AZD7762または0.5μM LY2603618)で処理した。洗浄により薬物を除去した後、細胞を、新しい培地で、37℃でさらに3日間、Chk1阻害剤の存在下でインキュベートした。AlamarBlueを用いて細胞生存力を測定した。ドキソルビシン群(ドキソルビシンもG2/M期における細胞周期停止を誘導し、これを非低酸素活性化プロドラッグ対照として使用した)について、細胞を、ドキソルビシンおよびChk1阻害剤で3日間共処理した。結果は、Hela細胞およびHT29細胞の両方において、TH-302活性は、Chk1阻害剤の存在により有意に高められたことを示した。Chk1阻害剤の存在下で、ドキソルビシン活性の同様の増強も観察された。得られたμMでのIC50値を図2に示す。
適切なDu145およびH460細胞を、実施例1に記載されるようにTH-302およびChk1阻害剤で処理した。結果は、Du145細胞およびH460細胞の両方において、TH-302活性は、Chk1阻害剤の存在により増強されれなかったことを示した。Chk1阻害剤の存在下でも、ドキソルビシン活性の活性増強の同様の欠如が観察された。これらの結果は、これらの細胞中のDNA修復を媒介するための機能的p53経路の存在と一致するものである。得られたμMでのIC50値を図2に示す。
細胞(Horizon Discovery Ltd.により提供され、Horizonのアデノ随伴ウイルス(AAV)技術GenesisTMを用いて作製された)を、実施例1に記載されるように処理した。結果は、p53欠陥細胞においては、Chk1阻害剤を用いた共処理によりTH-302活性は有意に増強されたが、p53を有する細胞においては増強されなかったことを示した。ドキソルビシンについても同様の結果が観察された。得られたμMでのIC50値を図2に示す。
HeLa細胞を、実施例1に記載されるように、TH-302およびChk1阻害剤で処理した。細胞を回収して、細胞周期破壊についてフローサイトメトリーにより、およびタンパク質発現についてイムノブロットにより分析した。結果は、TH-302は、G2/Mでの濃度依存的細胞周期停止を示し、TH-302により媒介されたG2/M停止は、Chk1阻害剤により排除され、TH-302媒介性G2/M停止におけるChk1キナーゼの役割が裏付けられることを示した。イムノブロットデータは、DNA損傷剤TH-302およびドキソルビシンにより、Cdc2-Y15のリン酸化が上方制御され、Chk1阻害剤により、DNA損傷剤誘導性のCdc2-Y15リン酸化の増加が完全に排除されたことを示した。Chk1阻害剤単独では、Cdc2-Y15リン酸化に影響を及ぼさなかった。
HT-29腫瘍保有マウスを、TH-302単独、AZD7762単独およびAZD7762と組み合わせたTH-302で処理した。TH-302は、50mg/kg、QDx5/週x2週間(毎日投与)または100mg/kg、2回/週x2週間(断続投与)のいずれかで腹腔内(i.p.)投与した。AZD7762は、12.5mg/kg、QDx5/週x2週間または12.5mg/kg、4回/週x2週間のいずれかでi.p.投与した。組み合わせ療法について、2種類の投与計画を使用した: QDx5/週x2週間でTH-302、および12.5mg/kg、QDx5/週x2週間でAZD7762、AZD7762は、TH-302投与の4時間後に投与した;ならびに100mg/kg、2回/週x2週間でTH-302、および12.5mg/kg、4回/週x2週間でAZD7762、AZD7762は、TH-302の4時間後および16時間後に投与した。データ(図4A〜Bに示す)は、TH-302単独またはAZD7762単独により、増殖遅延を生じたこと、およびAZD7762とTH-302の組み合わせにより、いずれかの薬物単独と比較して、腫瘍体積倍加に必要な時間が有意に延長されたことを示した。
前述の実施例は、Chk1阻害剤は、p53チェックポイント欠陥の背景で、インビトロおよびインビボの両方で、TH-302感作物質であることを示す。TH-302処理細胞におけるDNA損傷に対するChk1阻害剤AZD7762の影響を直接的に評価するために、一細胞電気泳動系「コメット」アッセイを使用した。HT29細胞を、1x106細胞/3ml/60mmディッシュで24時間播種した後、TH-302(以下に示す濃度で)および0.1μMのAZD7622を添加して、空気または0.1% O2下のいずれかで24時間インキュベートした。細胞を2回洗浄して化合物を除去した。コメットアッセイは、Trevigenの一細胞電気泳動系(Gaithersburg, MD)を使用して行った。Perceptive Instruments (Suffolk, UK)のComet Assay IVソフトウェアを使用して、オリーブテイルモーメントを計算した。オリーブテイルモーメントは、核のコアの本体からのDNA移動の距離であり、DNA損傷の程度の評価を示す。ビヒクル、TH-302(10μM、空気;2.5μM、0.1% O2)、またはAZD7762(0.1μM、空気)で処理した(24時間)HT29細胞は、認識できるテイルモーメントを示さなかった(0.1〜0.3のテイルモーメント値が観察された)。対照的に、AZD7762およびTH-302の両方で処理した細胞は、オリーブテイルモーメントを示し、二本鎖切断の誘導が示され、オリーブテイルモーメントは、3(空気中2.5μM TH-302および0.1μM AZD7762)〜25(0.1% O2中10μM TH-302および0.1μM AZD7762)の範囲であった。
Claims (11)
- 癌を治療するための方法であって、かかる治療を必要とする患者に、治療有効量のChk1阻害剤と組み合わせた治療有効量の低酸素活性化プロドラッグを投与する工程を含む、方法。
- 低酸素活性化プロドラッグが、式I:
Y2は、O、S、NR6、NCOR6またはNSO2R6であり、
R6は、C1-C6アルキル、C1-C6ヘテロアルキル、アリールまたはヘテロアリールであり;
R3およびR4は独立して、2-ハロアルキル、2-アルキルスルホニルオキシアルキル、2-ヘテロアルキルスルホニルオキシアルキル、2-アリールスルホニルオキシアルキルおよび2-ヘテロアルキルスルホニルオキシアルキルからなる群より選択され;
R1は、式L-Z3を有し;
Lは、C(Z1)2であり;
各Z1は独立して、水素、ハロゲン、C1-C6アルキル、C1-C6ヘテロアルキル、アリール、ヘテロアリール、C3-C8シクロアルキル、ヘテロシクリル、C1-C6アシル、C1-C6ヘテロアシル、アロイルもしくはヘテロアロイルであり;
またはLは:
Z3は:
各X1は独立して、NまたはCR8であり;
X2は、NR7、SまたはOであり;
各R7は独立して、C1-C6アルキル、C1-C6ヘテロアルキル、C3-C8シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり;
R8は独立して、水素、ハロゲン、シアノ、CHF2、CF3、CO2H、アミノ、C1-C6アルキル、C1-C6ヘテロアルキル、C1-C6シクロアルキル、C1-C6アルコキシ、C1-C6アルキルアミノ、C1-C6ジアルキルアミノ、アリール、CON(R7)2、C1-C6アシル、C1-C6ヘテロアシル、アロイルまたはヘテロアロイルである)
の化合物、またはその薬学的に許容され得る塩である、請求項1記載の方法。 - 前記式Iの化合物がTH-302である、請求項1または2記載の方法。
- 前記Chk1阻害剤が、AZD7762、LY2603618、PF-00477736およびSCH 900776からなる群より選択される、請求項1〜3いずれか記載の方法。
- 前記患者が、TH-302およびChk1阻害剤の投与前に、p53欠陥癌細胞を有すると同定される、請求項1〜4いずれか記載の方法。
- 式I:
Y2は、O、S、NR6、NCOR6またはNSO2R6であり、
R6は、C1-C6アルキル、C1-C6ヘテロアルキル、アリールまたはヘテロアリールであり;
R3およびR4は独立して、2-ハロアルキル、2-アルキルスルホニルオキシアルキル、2-ヘテロアルキルスルホニルオキシアルキル、2-アリールスルホニルオキシアルキルおよび2-ヘテロアルキルスルホニルオキシアルキルからなる群より選択され;
R1は、式L-Z3を有し;
Lは、C(Z1)2であり;
各Z1は独立して、水素、ハロゲン、C1-C6アルキル、C1-C6ヘテロアルキル、アリール、ヘテロアリール、C3-C8シクロアルキル、ヘテロシクリル、C1-C6アシル、C1-C6ヘテロアシル、アロイルもしくはヘテロアロイルであり;
またはLは:
Z3は:
各X1は独立して、NまたはCR8であり;
X2は、NR7、SまたはOであり;
各R7は独立して、C1-C6アルキル、C1-C6ヘテロアルキル、C3-C8シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり;
R8は独立して、水素、ハロゲン、シアノ、CHF2、CF3、CO2H、アミノ、C1-C6アルキル、C1-C6ヘテロアルキル、C1-C6シクロアルキル、C1-C6アルコキシ、C1-C6アルキルアミノ、C1-C6ジアルキルアミノ、アリール、CON(R7)2、C1-C6アシル、C1-C6ヘテロアシル、アロイルまたはヘテロアロイルである)
の化合物、またはその薬学的に許容され得る塩、
Chk1阻害剤、および少なくとも薬学的に許容され得る賦形剤
を含む、医薬製剤。 - 前記式Iの化合物がTH-302である、請求項6記載の医薬製剤。
- 前記Chk1阻害剤が、AZD7762、LY2603618、PF-00477736およびSCH 900776からなる群より選択される、請求項6または7記載の医薬製剤。
- 腫瘍細胞に、Chk1阻害剤を共投与する工程を含む、P53欠陥腫瘍細胞に対する式Iの化合物の抗腫瘍効果を増加させる方法。
- Chk1阻害剤が、AZD7762、PF477736またはLY603618である、請求項9記載の方法。
- 式Iの化合物がTH-302である、請求項9または10記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US201161579605P | 2011-12-22 | 2011-12-22 | |
US61/579,605 | 2011-12-22 | ||
US201261617576P | 2012-03-29 | 2012-03-29 | |
US61/617,576 | 2012-03-29 | ||
PCT/US2012/071074 WO2013096687A1 (en) | 2011-12-22 | 2012-12-20 | Administration of hypoxia activated prodrugs in combination with chk1 inhibitors for treating cancer |
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CA2990835A1 (en) * | 2015-06-23 | 2016-12-29 | Case Western Reserve University | Compositions and methods for treating cancer |
EP3631444A4 (en) * | 2017-06-01 | 2021-06-09 | Sierra Oncology, Inc. | BIOMARKERS AND PATIENT SELECTION STRATEGIES |
CA3140123A1 (en) * | 2019-05-14 | 2020-11-19 | Sierra Oncology, Inc. | Methods of treating cancer using chk1 inhibitors |
KR20240047452A (ko) | 2021-08-27 | 2024-04-12 | 아센타위츠 파마슈티컬즈 리미티드 | 동결건조 제형 용액과 동결건조 제형, 및 이의 방법과 용도 |
WO2023025312A1 (zh) | 2021-08-27 | 2023-03-02 | 深圳艾欣达伟医药科技有限公司 | 使用th-302治疗parp抑制剂耐药的患者 |
WO2023226959A1 (zh) * | 2022-05-23 | 2023-11-30 | 深圳艾欣达伟医药科技有限公司 | 烷化剂前药与细胞周期抑制剂联用治疗癌症的方法 |
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WO2013096687A1 (en) | 2013-06-27 |
EP2793882A4 (en) | 2015-04-29 |
JP2017218459A (ja) | 2017-12-14 |
EP2793882A1 (en) | 2014-10-29 |
US9254299B2 (en) | 2016-02-09 |
US20150005263A1 (en) | 2015-01-01 |
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