JP2020512977A - Chk1阻害剤とwee1阻害剤との組み合わせ - Google Patents
Chk1阻害剤とwee1阻害剤との組み合わせ Download PDFInfo
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Abstract
Description
本願は、米国仮出願第62/480,101号(2017年3月31日提出)の利益を主張する。本願は、すべての目的のためにその全体が参考として援用される。
本発明は、がんの処置に関する組成物、方法および使用を対象とする。種々の態様および実施形態は、一般に、Chk1阻害剤、例えば、Wee1阻害剤とのその組合せ、ならびにがんの処置においてそのような化合物および組合せを調製または使用する方法に関する。
がんは、合衆国および世界中で医療に相当な負荷を負わせ、社会に大きな影響を及ぼす疾患である。合衆国だけでも、2016年に160万人を超える人々が新たにがんを有すると診断され、約60万人ががんで死亡したと推定されている。がんは、身体における実質的にすべての細胞型から生じる腫瘍を含む非常に不均一な疾患であり、広範な環境的および遺伝的危険因子と関連している。さらに、がんは、すべての年齢、すべての民族、文化および社会経済学的群を襲う。
Chk1阻害剤は、単剤(single agent)としてまたは組合せ物でのいずれでも、例としてDNA損傷およびチェックポイント経路の構成的活性化が遺伝的不安定性を駆動している腫瘍細胞を処置することにおいて、有用である。種々の試みが、Chk1キナーゼの阻害剤を開発するために行われている。例えば、PCT出願公開第WO2003/010444号および第WO2005/072733号は、Chk1キナーゼ阻害剤としてアリール/ヘテロアリールウレア化合物を開示している。米国特許出願公開第2005/0215556号は、キナーゼ阻害剤として大環状ウレアを開示している。PCT出願公開第WO2002/070494号、第WO2006/014359号および第WO2006/021002号は、Chk1阻害剤としてアリールおよびヘテロアリールウレアを開示している。PCT出願公開第WO2011/141716号および第WO2013/072502号は、両方ともChk1阻害剤として置換ピラジニルフェニルウレアを開示している。PCT出願公開第WO2005/009435号および第WO2010/077758号は、Chk1キナーゼ阻害剤としてアミノピラゾールを開示している。
前述の努力にも関わらず、がん細胞をDNA損傷およびアポトーシス経路の活性化にさらに感受性にするため、ならびにがん細胞が他の化学療法および放射線治療による処置に耐性になりにくくするための治療剤として使用され得る、細胞周期チェックポイント阻害剤に対する必要は残ったままである。本発明は、これらの必要を満たし、関連する有利点をさらに提供する。
一部の態様では、本開示は、対象におけるがんを予防または処置するための方法であって、化合物1の治療有効量およびWee1阻害剤の治療有効量を対象に投与することを含む、方法を提供する。一部の実施形態では、Wee1阻害剤は、アダボセルチブ(adavosertib)(すなわち、AZD−1775)である。
I.序論
チェックポイントキナーゼ1(Chk1)は、SおよびG2相において細胞周期進行を停止することによって遺伝毒性ストレスに応答して細胞***を制御する、セリン/スレオニンタンパク質キナーゼである。Chk1の薬理学的阻害は、増加したDNA複製ストレスを有する腫瘍細胞を標的とし、DNA複製チェックポイント機能の解放(uncoupling)ならびにDNA損傷および細胞死の誘導をもたらす。これらの特性は、発がん性シグナル伝達および並行するDNA損傷応答経路機能の喪失によって駆動される高い複製ストレスを有するがんにおいてChk1阻害を、単剤としての新たな治療手法にする。
他を具体的に示す場合を除いて、本明細書で使用するすべての技術的および科学的用語は、本発明が属する技術分野の当業者によって一般に理解されるのと同じ意味を有する。加えて、本明細書に記載される方法または材料と類似のまたは等価の任意の方法または材料は、本発明の実施において使用され得る。本発明の目的のために、次の用語は定義される。
AZD−1775は、Wee1の高度に選択的、ATP競合的な、小分子阻害剤であり、酵素に対する約5.18nMのIC50を有する。in vitroでAZD−1775は、細胞に基づくアッセイにおいて約80nMのEC50を有して、Wee1活性を阻害し、DNA損傷およびG2チェックポイントエスケープを誘導する。p53−欠損細胞株において、AZD−1775は、ゲムシタビン、シスプラチン、カルボプラチンおよびトポテカンなどのDNA損傷剤との組合せで使用された場合に、細胞傷害性を増加させる。
A.がんを予防または処置するための方法
一態様では、本開示は、対象におけるがん(例えば、急性骨髄性白血病、食道がん、胃がん、マントル細胞リンパ腫、非小細胞肺がん(NSCLC)、卵巣がん、頭頸部がん、肝臓がん、膵臓がん、前立腺がんまたは中枢神経系がん)を予防または処置するための方法であって、対象にチェックポイントキナーゼ1(Chk1)阻害剤の治療有効量を投与することを含む方法を提供する。
B.医薬組成物
C.キット
本発明は、具体的な実施例の方法によってさらに詳細に記載される。続く実施例は、例示的目的のためだけに提供され、いかなる様式でも本発明を限定することを意図されない。当業者は、本質的に同じ結果を得るために変更または改変され得る種々の重要でないパラメーターを容易に認識する。
化合物1、新規、経口で利用可能なチェックポイントキナーゼ1阻害剤の薬物特性
化合物1は、その一部が図2に示されている多数の優れた薬物特性を示すChk1阻害剤である。特に化合物1は、限定的なオフターゲット活性を有してChk1に対してサブナノモル濃度の効力を示す。加えて、化合物1は、好ましい吸収、分布、代謝および排出(ADME)特性、薬物動態ならびに経口生体利用能を示す。7日間反復用量耐容性研究は、マウス、ラットおよびカニクイザルにおいて完了しており、カニクイザルサルGLP心血管系安全性研究(補正QT(QTc)間隔、左室圧(LVP)および収縮エンドポイントを含む)において所見はなかった。化合物1は、単剤として活性であるが、化学療法剤およびWee1阻害剤との組合せでも活性である。
化合物1の選択性および効力
化合物1の酵素選択性
化合物1を、図3Aに示すものを含む120個のキナーゼのパネルに対して1μM ATP濃度を使用してスクリーニングした。80%を超えて阻害されたすべてのキナーゼおよびChk2を図3Bに示す。各キナーゼについてATP Kmで測定したIC50値を、図3BにChk1と比較して示す。細胞IC50値を関連細胞株においてホスホエピトープ特異的抗体(phosphor-epitope-specific antibody)を使用するシグナル伝達アッセイから得た。
酵素アッセイを、10μMの[γ−33P]−ATPおよび、Reaction Biology Corp.から得た20μMのペプチド基質KKKVSRSGLYRSPSMPENLNRPR(配列番号1)を使用して実施した。図3Cに見られるとおり、IC50は0.124nMであった。
in vitroスクリーニング
多様ながん細胞株に対する詳細なスクリーニングを、単剤としての化合物1に感受性を示す腫瘍型を同定するために実施した。232個の癌由来細胞株のパネルを化合物1またはシスプラチンの希釈物を使用してハイスループット増殖アッセイにおいてスクリーニングした。細胞株を、30μMの開始濃度を使用して9つの用量レベルを達成した化合物1またはシスプラチンのhalf−log希釈物段階で処置し、72時間後にCellTiter−Glo(登録商標)アッセイ(Promega)を使用して増殖についてアッセイした。IC50(EC50)値を非線形回帰モデルを使用して用量応答データをフィッティングすることによって算出した。
NSCLC異種移植モデルにおけるin vivoスクリーニング
化合物1のin vivo有効性を評価するために、2つの異なるNSCLC異種移植モデルを使用した。SK−MES−1またはNCI−H727腫瘍細胞を胸腺欠損ヌードマウスの側腹部に皮下接種した。腫瘍が体積約200mm3に達したら、マウスを研究群(1群あたりn=10匹)に無作為化した。マウスを化合物1を1日あたり1回12.5、25または50mg/kgの用量で用いて経口経管栄養によって処置した。動物がビヒクルだけを投与された陰性対照群も含めた。
Wee1阻害剤との組合せでの化合物1の細胞スクリーニングおよび特徴付け
単剤としての化合物1の有効性を試験することに加えて、化合物1をWee1阻害剤AZD−1775との組合せで検査した。SK−MES−1およびNCI−H727腫瘍細胞を、用量設定した化合物1またはWee−1阻害剤AZD−1775の単独および組合せの両方を用いて処置した。細胞増殖をCellTiter−Glo(登録商標)アッセイ(Promega)を使用して薬物添加72時間後に測定した。図6A〜6Cに見られるとおり、化合物1とAZD−1775との組合せは、相乗効果を示した。さらに、活性の固有のパターンが薬物を単剤として検査した場合に観察された。
Wee1阻害剤との組合せでの化合物1のin vivo活性
NCI−H727 NSCLC腫瘍異種移植モデルを使用して、化合物1(1日1回25mg/kg)およびAZD−11775(1日1回30mg/kg)の両方を個々におよび組合せで、腫瘍の大きさを抑制するそれらの能力について検査した(図7Aおよび7B)。NCI−H727腫瘍細胞を胸腺欠損ヌードマウスの側腹部に皮下接種した。腫瘍が体積約200mm3に達したら、マウスを研究群(1群あたりn=10匹)に無作為化した。化合物1およびAZD−1775を経口経管栄養によって投与した。顕著な相乗効果が、2つの薬物を組み合わせた場合に観察された。
血液系腫瘍由来細胞株のハイスループットin vitroスクリーニング
約70個の造血細胞株のパネルを72時間増殖アッセイ(CrownBio Omnipanel)において化合物1への感受性についてスクリーニングした。スクリーニングした細胞株は、未分化大細胞リンパ腫(ALCL)、急性骨髄性白血病(AML)、B細胞急性リンパ芽球性白血病(B−ALL)、バーキットリンパ腫、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、マントル細胞リンパ腫(MCL)、多発性骨髄腫(MM)、急性前骨髄球性白血病(PML)、およびT細胞急性リンパ芽球性白血病(T−ALL)を示す細胞株を含んでいた。図8に示すとおり、化合物1による抑制に特に感受性であった血液系腫瘍由来細胞株のサブセットは、MCLおよびAML細胞株を含んでいた。
MCL細胞株における抗増殖活性
マントル細胞リンパ腫(MCL)は、稀であり、通常は、合衆国においておよそ15,000名の患者を冒す非ホジキンリンパ腫の高悪性度形態である。大多数のMCL患者は、サイクリンD1の過剰発現をもたらすt(11;14)(q13;q32)の染色体転座を保有する。Chk1およびWee1キナーゼがCdk/サイクリン活性の制御因子であることから、MCLは、Chk1阻害剤単独にまたはWee1阻害剤との組合せに固有に感受性にされ得る。
MCL異種移植モデルにおける単剤としての化合物1
化合物1の効果を2つの異なるマントル細胞リンパ腫(MCL)異種移植モデルにおいて評価した。Jeko−1およびまたはMaver−1細胞をCB17.SCIDマウス(Jeko−1細胞について)または胸腺欠損ヌードマウス(Maver−1細胞について)の側腹部に皮下接種した。腫瘍が体積約200mm3に達したら、マウスを研究群(1群あたりn=10匹)に無作為化した。マウスを経口経管栄養によって化合物1を用いて、または陰性対照としてビヒクルだけを用いて処置した。ある処置群では、化合物1を1日1回、21日間投与した。他の処置群では、化合物1を1日2回、3サイクル投与し、各サイクルは、3日間連続の処置に続く4日間連続の無処置で構成された。
MCL細胞株における化合物1とWee1阻害剤との相乗性
いくつかのマントル細胞リンパ腫(MCL)細胞株において、化合物1とWee1阻害剤とを組み合わせることの効果を試験するために、in vitroアッセイを実施した。MCL細胞を、漸増濃度の化合物1と組み合わせた、用量設定したWee1阻害剤、AZD−1775を用いて処置した。増殖を72時間で測定した。阻害がJeko−1(図11A)、Maver−1(図11B)およびZ−138(図11C)細胞株のアッセイにおいて観察された。
MCL細胞株におけるDNA損傷およびアポトーシス誘導
DNA損傷を誘導する化合物1の能力を評価するために、マントル細胞リンパ腫(MCL)細胞株を、用量設定した化合物1単独またはWee1阻害剤AZD−1775との組合せを用いて18時間処置した。細胞を溶解し、ホスホ−H2A.X(S139)レベルを免疫ブロットによってアッセイし、LI−COR Odyssey imagerで検出した。図12に示すとおり、化合物1は、複数のMCL細胞株(Jeko−1、Z−138およびMaver−1細胞)においてDNA損傷を誘導し、DNA損傷誘導が、Wee1が同時に阻害される場合に増強された。
化合物1とWee1阻害剤との組合せのin vivo研究
Jeko−1マントル細胞リンパ腫(MCL)腫瘍異種移植モデルを化合物1およびWee1阻害剤を用いたChk1阻害の組合せ効果を研究するために使用した。Jeko−1細胞をCB17.SCIDマウスの側腹部に皮下接種した。腫瘍が体積約200mm3に達したら、マウスを研究群(1群あたりn=10匹)に無作為化した。マウスを化合物1(7.5mg/kg)、AZD−1775(15mg/kg)または両方を用いて、経口経管栄養によって1日1回、3サイクル処置した(各サイクルは、3日間連続の処置に続く4日間連続の無処置で構成された)。マウスがビヒクルだけによって処置される陰性対照群を含んだ。
AML細胞株における化合物1活性のin vitro研究
急性骨髄性白血病(AML)細胞への化合物1の効果を試験するために、いくつかのAML細胞株を化合物1のhalf−log段階希釈物を用いて96ウエルフォーマットにおいて処置し、CellTiter−Glo(登録商標)アッセイ(Promega)を使用して72時間後に増殖についてアッセイした。図15Aおよび15Bにおいて示されるとおり、化合物1は、複数のAML細胞株において抗増殖活性を実証した。
AML細胞における化合物1活性のin vivo研究
MV−411腫瘍異種移植モデルを、AML腫瘍成長をin vivoで阻害する化合物1の能力を検査するために使用した。MV−411細胞をMatrigelと1:1の比で混合し、メスNOD.SCIDマウスの右側腹部に皮下注射した。腫瘍が体積約100から200mm3に達したら、マウスを研究群(1群あたりn=10匹)に無作為化し、経口経管栄養によって化合物1を投薬した。
Claims (28)
- 対象におけるがんを予防または処置するための方法であって、(i)化合物1または薬学的に許容されるその塩;および(ii)Wee1阻害剤または薬学的に許容されるその塩の治療有効量を前記対象に投与することを含む、方法。
- 前記Wee1阻害剤がAZD−1775である、請求項1に記載の方法。
- 前記がんが、急性骨髄性白血病、食道がん、胃がん、マントル細胞リンパ腫、非小細胞肺がん(NSCLC)、卵巣がん、頭頸部がん、肝臓がん、膵臓がん、前立腺がんおよび中枢神経系がんからなる群から選択される、請求項1または2に記載の方法。
- 前記がんが転移性がんである、請求項1から3のいずれか一項に記載の方法。
- 前記がんが多剤耐性がんである、請求項1から4のいずれか一項に記載の方法。
- 化合物1の用量が、前記対象の体重1kgあたり約1mgから100mgの間である、請求項1から5のいずれか一項に記載の方法。
- 前記化合物1の用量が、前記対象の体重1kgあたり約12.5mgである、請求項6に記載の方法。
- 前記化合物1の用量が、前記対象の体重1kgあたり約25mgである、請求項6に記載の方法。
- 前記化合物1の用量が、前記対象の体重1kgあたり約50mgである、請求項6に記載の方法。
- 前記AZD−1775の用量が前記対象の体重1kgあたり約30mgである、請求項2から9のいずれか一項に記載の方法。
- 前記化合物1の用量が前記対象の体重1kgあたり約25mgであり、前記AZD−1775の用量が前記対象の体重1kgあたり約30mgである、請求項6から10のいずれか一項に記載の方法。
- 化合物1および前記Wee1阻害剤が共投与される、請求項1から11のいずれか一項に記載の方法。
- 化合物1および前記Wee1阻害剤が同時にまたは連続的に共投与される、請求項12に記載の方法。
- 化合物1または前記Wee1阻害剤が経口、静脈内、筋肉内、皮下または腫瘍内に投与される、請求項1から13のいずれか一項に記載の方法。
- 前記対象を処置することが、腫瘍体積の低減をもたらす、請求項1から14のいずれか一項に記載の方法。
- 前記対象を処置することが、がんの1つまたは複数の徴候または症状の減少または除去をもたらす、請求項1から15のいずれか一項に記載の方法。
- 前記対象を処置することが、生存時間の増加をもたらす、請求項1から16のいずれか一項に記載の方法。
- 前記対象ががんを有さない、請求項1から14のいずれか一項に記載の方法。
- DNA損傷剤を投与することをさらに含む、請求項1から14のいずれか一項に記載の方法。
- (i)化合物1または薬学的に許容されるその塩;
(ii)Wee1阻害剤または薬学的に許容されるその塩;および
(iii)薬学的に許容される担体
を含む、医薬組成物。 - 前記Wee1阻害剤がAZD−1775である、請求項19に記載の医薬組成物。
- 化合物1が約0.1nMから2,000nMの間の濃度で存在する、請求項20または21に記載の医薬組成物。
- AZD−1775が約0.1nMから1,000nMの間の濃度で存在する、請求項21または22に記載の医薬組成物。
- DNA損傷剤を含む、請求項19から22のいずれかに記載の医薬組成物。
- 請求項20から23のいずれか一項に記載の医薬組成物を含む、対象におけるがんを予防または処置するためのキット。
- 使用のための指示をさらに含む、請求項25に記載のキット。
- 1つまたは複数の試薬をさらに含む、請求項25または26に記載のキット。
- 前記組成物がDNA損傷剤を含む、請求項25から27のいずれかに記載のキット。
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- 2018-03-30 US US16/498,351 patent/US20200108074A1/en not_active Abandoned
- 2018-03-30 EP EP18718379.3A patent/EP3600247A1/en not_active Withdrawn
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JP2013542997A (ja) * | 2010-11-16 | 2013-11-28 | アレイ バイオファーマ、インコーポレイテッド | チェックポイントキナーゼ1阻害剤とwee1キナーゼ阻害剤の組み合わせ |
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MX2019011506A (es) | 2019-11-01 |
EP3600247A1 (en) | 2020-02-05 |
US20200108074A1 (en) | 2020-04-09 |
SG11201908788YA (en) | 2019-10-30 |
KR20190130621A (ko) | 2019-11-22 |
AU2018243667A1 (en) | 2019-10-17 |
IL269409A (en) | 2019-11-28 |
CN110678169A (zh) | 2020-01-10 |
CA3058457A1 (en) | 2018-10-04 |
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