JP2017532312A - 癌を治療するための併用療法 - Google Patents
癌を治療するための併用療法 Download PDFInfo
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- JP2017532312A JP2017532312A JP2017514624A JP2017514624A JP2017532312A JP 2017532312 A JP2017532312 A JP 2017532312A JP 2017514624 A JP2017514624 A JP 2017514624A JP 2017514624 A JP2017514624 A JP 2017514624A JP 2017532312 A JP2017532312 A JP 2017532312A
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Abstract
Description
本出願は、2014年9月17日に提出された米国仮特許出願第62/051,890号明細書;2014年12月5日に提出された米国仮特許出願第62/088,498号明細書;2015年2月4日に提出された米国仮特許出願第62/112,086号明細書;2015年5月21日に提出された米国仮特許出願第62/165,169号明細書;および2015年8月10日に提出された米国仮特許出願第62/203,285号明細書に対する優先権およびその利益を主張する。これらの特許出願の各々の内容全体を参照により全体を本明細書に援用する。
またはその薬学的に許容される塩および1つまたは複数の治療剤を含む併用を特徴とし、
式中、
Tは6〜10個の炭素原子のリンカー基であり、1個または複数個の炭素原子はヘテロ原子で任意選択的に置き換えられており、Tは任意選択的に置換されており;
R9は、C6〜C10アリール、または非置換もしくは置換t−ブチル、CF3、シクロヘキシル、C6〜C10アリールおよび5〜10員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換された5〜10員ヘテロアリールを含み;
AはOまたはCH2であり;
GおよびJは各々独立にH、ハロ、C(O)OH、C(O)O−C1〜C6アルキルまたはORaであり、RaはH、C1〜C6アルキル、C(O)−C1〜C6アルキルまたはシリルであり、C(O)O−C1〜C6アルキル、C1〜C6アルキルまたはC(O)−C1〜C6アルキルはハロ、シアノヒドロキシル、カルボキシル、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノおよびC3〜C8シクロアルキルからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;
Xは各々独立にNまたはCRxであり、RxはH、ハロ、ヒドロキシル、カルボキシル、シアノまたはRS1であり、RS1はアミノ、C1〜C6アルコキシル、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルまたは5〜6員ヘテロアリールであり、かつRS1はハロ、ヒドロキシル、カルボキシル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルおよび5〜6員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;
R1およびR2は各々独立にH、ハロ、ヒドロキシル、カルボキシル、シアノまたはRS2であり、RS2はアミノ、C1〜C6アルコキシル、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニルまたはC3〜C8シクロアルキルであり、かつRS2は各々、ハロ、ヒドロキシル、カルボキシル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルおよび5〜6員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;
R8はH、ハロまたはRS3であり、RS3はC1〜C6アルキル、C2〜C6アルケニルまたはC2〜C6アルキニルであり、かつRS3はハロ、ヒドロキシル、カルボキシル、シアノアミノ、C1〜C6アルコキシル、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノおよびC3〜C8シクロアルキルからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;かつ
QはH、NH2、NHRb、NRbRc、Rb、=O、OHまたはORbであり、RbおよびRcは各々独立にC1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C8シクロアルキル、C6〜C10アリール、4〜7員ヘテロシクロアルキル、5〜10員ヘテロアリールまたは−M1−T1であり、M1は結合、またはハロ、シアノ、ヒドロキシルもしくはC1〜C6アルコキシルで任意選択的に置換されているC1〜C6アルキルリンカーであり、T1はC3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルまたは5〜10員ヘテロアリールであり、あるいは、RbおよびRcはそれらが結合しているN原子と一緒になって、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、ハロ、ヒドロキシル、カルボキシル、C(O)OH、C(O)O−C1〜C6アルキル、OC(O)−C1〜C6アルキル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルまたは5〜6員ヘテロアリールで任意選択的に置換された、N原子に加えて0または1個のヘテロ原子を有する4〜7員ヘテロシクロアルキルを形成し、Rb、RcおよびT1は各々C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、ハロ、ヒドロキシル、カルボキシル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルおよび5〜6員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換されている。
(式中、
Tは6〜10個の炭素原子のリンカー基であり、1個または複数個の炭素原子はヘテロ原子で任意選択的に置き換えられており、Tは任意選択的に置換されており;
R9は、C6〜C10アリール、または非置換もしくは置換t−ブチル、CF3、シクロヘキシル、C6〜C10アリールおよび5〜10員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換された5〜10員ヘテロアリールを含み;
AはOまたはCH2であり;
GおよびJは各々独立にH、ハロ、C(O)OH、C(O)O−C1〜C6アルキルまたはORaであり、RaはH、C1〜C6アルキル、C(O)−C1〜C6アルキルまたはシリルであり、C(O)O−C1〜C6アルキル、C1〜C6アルキルまたはC(O)−C1〜C6アルキルはハロ、シアノヒドロキシル、カルボキシル、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノおよびC3〜C8シクロアルキルからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;
Xは各々独立にNまたはCRxであり、RxはH、ハロ、ヒドロキシル、カルボキシル、シアノまたはRS1であり、RS1はアミノ、C1〜C6アルコキシル、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルまたは5〜6員ヘテロアリールであり、かつRS1はハロ、ヒドロキシル、カルボキシル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルおよび5〜6員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;
R1およびR2は各々独立にH、ハロ、ヒドロキシル、カルボキシル、シアノまたはRS2であり、RS2はアミノ、C1〜C6アルコキシル、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニルまたはC3〜C8シクロアルキルであり、かつRS2は各々、ハロ、ヒドロキシル、カルボキシル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルおよび5〜6員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;
R8はH、ハロまたはRS3であり、RS3はC1〜C6アルキル、C2〜C6アルケニルまたはC2〜C6アルキニルであり、かつRS3はハロ、ヒドロキシル、カルボキシル、シアノアミノ、C1〜C6アルコキシル、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノおよびC3〜C8シクロアルキルからなる群から選択される1つまたは複数の置換基で任意選択的に置換されており;かつ
QはH、NH2、NHRb、NRbRc、Rb、=O、OHまたはORbであり、RbおよびRcは各々独立にC1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C8シクロアルキル、C6〜C10アリール、4〜7員ヘテロシクロアルキル、5〜10員ヘテロアリールまたは−M1−T1であり、M1は結合、またはハロ、シアノ、ヒドロキシルもしくはC1〜C6アルコキシルで任意選択的に置換されているC1〜C6アルキルリンカーであり、T1はC3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルまたは5〜10員ヘテロアリールであり、あるいは、RbおよびRcはそれらが結合しているN原子と一緒になって、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、ハロ、ヒドロキシル、カルボキシル、C(O)OH、C(O)O−C1〜C6アルキル、OC(O)−C1〜C6アルキル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルまたは5〜6員ヘテロアリールで任意選択的に置換された、N原子に加えて0または1個のヘテロ原子を有する4〜7員ヘテロシクロアルキルを形成し、Rb、RcおよびT1は各々C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、ハロ、ヒドロキシル、カルボキシル、シアノ、C1〜C6アルコキシル、アミノ、モノC1〜C6アルキルアミノ、ジC1〜C6アルキルアミノ、C3〜C8シクロアルキル、C6〜C10アリール、4〜6員ヘテロシクロアルキルおよび5〜6員ヘテロアリールからなる群から選択される1つまたは複数の置換基で任意選択的に置換されている)
またはその薬学的に許容される塩、多形、溶媒和物、もしくは立体異性体を提供する。
を有するDOT1L阻害剤化合物A2(「Cpd A2」もしくはピノメトスタットもしくは「5676」もしくは「EPZ−5676」とも呼ばれる)またはその薬学的に許容される塩、多形、溶媒和物、もしくは立体異性体を含む。
を有するDOT1L阻害剤化合物D16(「化合物T」もしくは「EPZ−4777」とも呼ばれる)またはその薬学的に許容される塩、多形、溶媒和物、もしくは立体異性体を含む。
)、ファルネシルトランスフェラーゼ阻害剤(たとえばティピファニブ)、PLK1阻害剤(たとえばボラセルチブ)、または本明細書において開示される治療剤のいずれかの併用を含む。
またはその薬学的に許容される塩、多形、溶媒和物、もしくは立体異性体および1つまたは複数の他の治療剤を含む組成物が、疾患または癌の治療を必要とする被検体に投与される、併用療法のための方法を提供する。この併用療法はまた、増殖を阻害するまたは細胞死を誘導するために、癌細胞に対して施すことができる。
を有する化合物A2(EPZ−5676としても知られている)またはその薬学的に許容される塩、多形、溶媒和物、もしくは立体異性体および1つまたは複数の治療剤を含む医薬組成物を提供する。
を有する化合物D16(化合物TおよびEPZ−4777としても知られている)またはその薬学的に許容される塩、多形、溶媒和物、もしくは立体異性体および1つまたは複数の治療剤を含む医薬組成物を提供する。
方法
急性骨髄性白血病細胞株のMV4−11(MLL−AF4)およびMOLM−13(MLL−AF9)をそれぞれ、American Type Culture Collection(ATCC;Rockville,MD)およびDeutsche Sammlung von Mikroorganismen and Zellkulturen(DSMZ;Braunschweig,Germany)から入手した。MV4−11細胞は、IMDM(Invitrogen、10%熱不活化ウシ胎児血清(Life Technologies,Grand Island,NY)を添加)中で維持し、MOLM−13細胞は、10%ウシ胎児血清(Life Technologies,Grand Island,NY)を添加したRPMI−1640中で維持した。5%CO2を含む加湿雰囲気中で培養物を維持した。
化合物について、そのIC50値周辺を含む濃度範囲で化合物を試験することによって、同時処理段階における相乗作用を評価した。この試験では、各化合物単独の効果に加えて、一定比で併用する各薬物を増加する濃度で含むマトリックス形式で96ウェルプレートに化合物を入れた(図3)。細胞を播種し、同時処理段階において3または7日間、対数直線期で増殖させた。試験ウェルの作用を受けた割合(fraction affected)(Fa)を計算するために、各プレートに最小阻害(DMSO単独)対照を用いた。DMSO濃度は0.1%v/vに維持した。
急性白血病に対する現行の標準治療薬および他のクロマチン修飾薬との併用における化合物A2の活性を、3種のヒト急性白血病細胞株;Molm−13(MLL−AF9を発現する急性骨髄性白血病(AML))、MV4−11(MLL−AF4を発現する急性混合性白血病細胞株)およびSKM−1(非MLL再構成AML)における細胞増殖アッセイで評価した。統計的に意味のある結果が得られるように、複数のレプリケートポイントを有する2つの薬剤の完全な用量設定マトリックスの抗増殖活性の試験に適した高密度併用プラットフォームを確立した。このプラットフォームを用いて、第2の薬剤をアッセイの開始時に化合物A2と一緒に加える同時処理モデル、または第2の薬剤の添加前に、細胞を化合物A2の存在下で数日間インキュベートする前処理モデルで試験した化合物A2の抗増殖作用を評価した。薬物併用解析は、Chou−Talalay法[Chou TC Pharmacological Reviews 2006]を用いて行なった。Fa−CIプロットとして知られる併用指数(CI)対分割効果(Fa)の値を示すグラフを作成し、相乗作用を評価した。薬物相乗作用は1未満のCI値によって、拮抗作用はCI>1によって、相加作用はCI=1によって統計的に定義される。
化合物A2は、MLL再構成を有する急性白血病に対する有望な療法として現在臨床試験中である、ヒストンメチルトランスフェラーゼDOT1Lの小分子阻害剤である。遺伝子ノックアウトおよび小分子阻害剤試験から、DOT1Lが、モデル系においてMLL融合タンパク質介在性の白血病誘発に必要であることが実証された。前臨床試験では、化合物A2は、インビトロにおいて、MLL遺伝子転座のない急性白血病株を除外した、MLL転座を有する急性白血病株の細胞致死を促進し、またMLL再構成白血病のラット異種移植モデルにおいて持続的な腫瘍退縮をもたらした[Daigle et al.Blood 2013]。有望な将来の臨床的シナリオを支援するために、急性白血病の現行の標準治療薬および他のクロマチン修飾薬と併用した化合物A2の活性を、3種のヒト急性白血病細胞株;Molm−13(MLL−AF9発現する急性骨髄性白血病(AML))、MV4−11(MLL−AF4発現する急性混合性白血病細胞株)およびSKM−1(非MLL再構成AML)について細胞増殖アッセイで評価した。ここで、統計的に意味のある結果が得られるように、複数のレプリケートポイントを有する2つの薬剤の完全な用量設定マトリックスの抗増殖活性の試験に適した高密度併用プラットフォームを確立した。このプラットフォームを用いて、第2の薬剤をアッセイの開始時に化合物A2と一緒に加える同時処理モデル、または第2の薬剤の添加前に、細胞を化合物A2の存在下で数日間インキュベートする前処理モデルで試験した化合物A2の抗増殖作用を評価した。薬物併用解析は、Chou−Talalay法[Chou TC Pharmacological Reviews 2006]を用いて行なった。Fa−CIプロットとして知られる併用指数(CI)対分割効果(Fa)の値を示すグラフを作成し、相乗作用を評価した。薬物相乗作用は1未満のCI値によって、拮抗作用はCI>1によって、相加作用はCI=1によって統計的に定義される。
A)96ウェル形式での前処理モデル:
ヒト白血病細胞株を、7濃度の化合物A2またはDMSOにより、4日間(MV4−11細胞)または7日間(MOLM−13細胞)フラスコ中で前処理した。次いで、細胞をカウントし、化合物A2と共にまたは化合物A2なしで(化合物A2ウォッシュアウト)、濃度を増加させた第2の薬剤の存在下、96ウェルプレートに一定の細胞密度でさらに3日間再播種した。HP−D300デジタルディスペンサー(Tecan)を用いて、組合せマトリックスに化合物を分注した。各化合物単独のIC50の上下を含む複数濃度の化合物A2および標準治療薬で細胞を処理した。細胞生存率を、CellTiter−Glo(登録商標)(Promega)を用いて、ATP含量により測定した。
ヒト白血病細胞株を、7濃度の化合物A2および9濃度の目的化合物のマトリックスで7日間処理した。生存率をCellTiter−Glo(登録商標)(Promega)を用いて決定した。
MOLM−13細胞を、7濃度の化合物A2またはDMSOビヒクル対照で7日間、フラスコ中で前処理した。次いで、細胞をカウントし、相乗的な細胞致死活性を与えることが以前に実証されている濃度の化合物A2およびAra−Cの存在下、一定の細胞密度で再播種し、さらに3または7日間インキュベートした。Guava EasyCyte HT(商標)フローサイトメーターを用いて、DNA含量、アネキシンV染色ならびにCD14マーカーおよびCD11bマーカーの細胞表面発現を10および14日目に測定した。
(1)化合物A2は、AML SOC薬のAra−Cおよびダウノルビシンと相乗的に作用して、MLL再構成白血病細胞に選択的である強力な抗増殖反応を誘導する;
(2)相乗作用は、化合物A2がAra−Cおよびダウノルビシンの追加前にウォッシュアウトされる場合でも、観察される;
(3)初期の試験から、アポトーシスおよび分化の同時誘導がMLL再構成白血病細胞株MOLM−13においてSOC薬について観察された併用有益性の基礎となることが示唆される;また
(4)MLL再構成白血病細胞株における相乗的な抗増殖活性は、化合物A2が、DNAメチルトランスフェラーゼ阻害剤アザシチジンおよびデシタビンならびにブロモドメイン阻害剤i−BETを含むいくつかのクロマチン修飾剤と併用される場合にも観察される。
図26Dに示すように、96ウェル形式において添加順序を逆にした前処理モデルを以下のとおりに実施する。
細胞をAra−Cで前処理した後、化合物A2と同時処理した場合に相乗作用が観察される。Ara−Cが化合物A2による処理前にウォッシュアウトされる場合にも、併用有益性が維持される。
材料および方法
細胞株
急性骨髄性白血病細胞株MV4−11(MLL−AF4)(CRL−9591)は、American Type Culture Collection(ATCC)、Manassas,VAから入手し、MOLM−13(MLL−AF9)細胞(ACC554)およびSKM−1(ACC547)細胞は、Leibniz Institute DSMZ−German Collection of Microorganisms and Cell Cultures,Braunschweig,Germanyから入手した。MV4−11細胞は、10%ウシ胎児血清を添加したIMDM中で維持した。MOLM−13およびSKM−1細胞は、10%ウシ胎児血清を添加したRoswell Park Memorial Institute培地(RPMI)中で維持した。これらの細胞は、加湿した5%CO2雰囲気中、フラスコまたはプレートで培養した。
細胞増殖に対する2薬剤一緒の併用の癌細胞致死効果を評価するために、MOLM−13、MV4−11およびSKM−1細胞株を用いてインビトロで増殖試験を行った。最初の増殖試験は、各細胞株における所与の化合物のIC50値を決定するために行なった。細胞数は、Promega Cell Titer Gloキットおよび所与のウェルにおけるATP量に対応したルミネセンス値を用いるATP定量により測定した。
0日目に、MOLM−13細胞を3,000細胞/mLで播種する。7日目および10日目に、MOLM−13細胞をカウントし、50,000細胞/mLで再播種する。MOLM−13細胞を、種々の濃度の化合物で単剤として、またはAraCもしくはダウノルビシンと併用して処理した。1〜7日目は、化合物A2のみで細胞を処理した。7日目に細胞を再播種し、以下に記載のように、化合物A2を単独またはAra−Cもしくはダウノルビシンと併用して再投与した。10日目に、それらをさらに再投与した。14日目に、実験を終了した。7、10および14日目に、CD14およびCD11bの解析のために細胞を採取した。
各細胞周期にある細胞の割合を評価するために、フローサイトメトリー解析を行った。アポトーシスによる細胞死の検出および細胞周期についてFACS解析を行った。化合物A2により単独でまたは併用で細胞を処理した。細胞周期とアポトーシスの同時解析を可能にするために、化合物A2により単独でまたは併用で細胞を処理した。
分化の程度を解析するために、MOLM−13細胞を0.1%DMSOもしくは以前に記載した濃度の化合物A2、Ara−C、ダウノルビシンの存在下、または併用してインキュベートした。7、10および14日目に、細胞を解析のために回収した。細胞をPBS中で2回洗浄した後、4%ホルムアルデヒド中、37℃で10分間固定することにより調製した。固定後、細胞を洗浄し、室温で10分間、ブロッキングバッファーでブロックした。次いで抗CD14抗体、抗CD11b抗体または抗IgG抗体の存在下、回転させながら、室温で1時間、細胞をインキュベートした。細胞を洗浄し、PBSに再懸濁し、GuavaCyte Plus System上のExpressProソフトウェアを用いて、5,000イベントを解析した。
分化またはアポトーシス細胞死のマーカーについて細胞集団をさらに解析するために、MOLM−13細胞を、5、7、8、9、10、11、12および14日目にイメージング用に回収した。細胞を被験物質とインキュベートし、各時点で細胞を回収し、PBSで1回洗浄し、0.5%BSA+PBSブロッキングバッファーに再懸濁した。1:12.5の稀釈のCD11b抗体を、暗所にて37℃で15分間、回転させながら細胞とインキュベートした。培地Aを加え、細胞をさらに15分間インキュベートした。PBS+0.1%NaN3+5%FBSで1回洗浄した後、細胞をFixおよびPermキットからの培地Bに再懸濁した。1:100,000稀釈のDAPIおよび1:50稀釈の第2の抗体(カスパーゼ−3またはH2A.X)を加え、暗所にて室温で20分間、細胞をインキュベートした。最後のインキュベーション後、PBS+0.1%NaN3+5%FBSで1回細胞を洗浄し、150μLのPBSに再懸濁し、約30〜60分間プレート上で沈降させた後、イメージングを行った。
化合物A2は、AML標準治療薬との併用で相乗的および持続的抗増殖効果を誘導する
化合物A2は、MLL再構成白血病細胞株MOLM−13およびMV4−11において、AMLの2種の標準治療(SOC)薬シタラビンおよびダウノルビシンとの併用で相乗的な抗増殖活性を示す(図28)。上記に記載の前処理モデルに従って細胞を処理した(すなわち、化合物A2のウォッシュアウトなし)。同時処理モデルに従って細胞を処理した場合にも、AML SOC薬との併用で化合物A2の相乗的な抗増殖活性が観察された。興味深いことには、この相乗的な抗増殖活性は、化合物A2がSOC薬の追加前に除去(すなわち、ウォッシュアウト)された場合でも、MOLM−13およびMV4−11のMLL再構成細胞において維持された(図29)。これらのデータは、DOT1L阻害剤が細胞環境から除去された場合でも、これらの細胞を化学療法剤に対して一層急性的に感受性にさせる、化合物A2による、これらの細胞のエピジェネティックな状態の持続的なリプログラミングを意味するという点で注目すべきである。この結果は、DOT1L基質部位のH3K79でのヒストンメチル化に対する化合物A2の効果のカイネティクスと一致している(Daigle et al,2013)。以前の試験において、化合物A2による4日間処理がH3K79me2の細胞レベルを80%超枯渇させるのに十分であることを示した。次いで、これらの細胞からウォッシュアウトにより化合物A2が除去された場合、H3K79メチル化の回復はウォッシュアウト後3日間観察されなかった。この3日間の潜在期間後、H3K79me2のレベルは、その後の4日間にわたって前処理レベルに徐々に戻った。したがって、化合物A2によるMLL再構成細胞の処理により、化学療法誘導の細胞致死に対してこれらの細胞を感作する、H3K79メチル化の持続的な阻害がもたらされる。これらの結果は、化合物A2と化学療法の併用に関する高度に柔軟な投薬スケジュールの可能性を提供する。
化合物A2は、単剤として、MOLM−13細胞の7日間処理後にアポトーシス細胞(アネキシンV染色により測定される)の濃度依存的な増加を誘導する。図32Aに示すように、生細胞の総数は、古典的なラングミュア等温線に従って化合物Aの濃度と共に減少し、中央値(EC50)として364±18nMが得られるが、この傾向は、アポトーシス細胞(初期および後期アポトーシスの合計)の含量の増加に正確に反映される。アポトーシス誘導のカイネティクスは、DMSO(対照として)、156nMの化合物A2、63nMのシタラビン(Ara−C)または化合物A2とAra−C(単剤処理と同じ濃度)の併用で処理する、MOLM−13細胞に対する14日間処理にわたって定時ポイントで測定した。Ara−Cは単独で、14日間の処理期間にわたってアポトーシス細胞集団の中程度の増加を誘導したが、化合物A2は、同じ時間経過中にアポトーシスのさらに一層激しい誘導をもたらした。この2つの薬物の併用により、MOLM−13細胞においてアポトーシスが増強された(図32B)。アポトーシス細胞含量はまた、細胞周期のサブG1期にある細胞のパーセントを測定することにより評価した。図32Cに、DMSO(対照)、156nMの化合物A2、63nMのAra−Cまたは化合物A2とAra−Cの併用で処理したMOLM−13細胞についての種々の時点での細胞周期段階の分布を示す。サブG1細胞集団に対するデータはまた、図32Dにカイネティックプロットとして図示する。このプロットから、Ara−C処理単独では、14日間の処理期間にわたって、MOLM−13細胞のサブG1集団は最小限の影響しか受けなかったが、化合物A2による処理では、サブG1集団の中程度の時間依存的増加が得られることが明らかになる。化合物A2とAra−Cを併用すると、10および14日目に、サブG1細胞集団の顕著な増加が、サブG1集団の増殖速度の増加も伴って得られる。同様の結果は、化合物A2をダウノルビシンと併用した場合にも観察された。
MLL−rはまた、急性リンパ性白血病(ALL)において見つけられ、乳児(12月齢よりも幼い子供)に主として関連する。11q23転座を有していないALL患者と比較した場合、この一部のALLは予後不良を有する。MLL−rを持つ乳児において長期的にイベントがない生存は28〜45%であることが報告された。これらの割合は、90%に近い生存率を有する非MLL−r患者よりもはるかに低い(Pieters et al.,Lancet 370:240−250,2007;Bhojwani et al.,Clin Lymphoma Myeloma 9(Suppl 3):S222−S230 10.3816/CLM.2009.s.016,2009;Inaba et al.,Lancet 381:1943−1955,2013)。AML SOCと同様に、実験は、ミトキサントロン、メトトレキサート、マホスファミド、プレドニゾロン、およびビンクリスチンを含む現行のALL療法と化合物A2の併用を評価するために実行した(Pieters et al.,2007;Inaba et al.,2013)。これらの併用の結果を表4に要約する。相乗作用または相加効果は、プレドニゾロンを除いて化合物A2と併用したすべてのALL SOC薬剤で観察され、拮抗作用は、MLL−r細胞株において観察された。ALL SOC薬剤の抗増殖単剤活性の増強は、プレドニゾロンを除いて非MLL−r細胞株SKM−1において化合物A2と併用した場合、見られず、抗増殖活性の増強は、1000nMを超える化合物A2濃度の存在下において観察された。プレドニゾロン活性におけるこの増強の根拠は不明である;しかしながら、使用したこれらの化合物A2濃度が、前臨床MLL−rモデルにおける最大の効能に必要とされるものよりもはるかに高いことは注意すべきことである。
化合物A2は、ヒト臨床試験で試験される最初のタンパク質メチルトランスフェラーゼ(PMT)阻害剤である。PMT標的クラスは、ヒストンH3およびH4上のリジン残基の部位特異的メチル化によりクロマチンリモデリングおよび遺伝子転写プログラミングをもたらす。DOT1Lの場合、酵素は、単一ヒストン部位H3K79のメチル化を唯一触媒する。遺伝子転写のエピジェネティックな調節は、ヒストンメチル化、ヒストンアセチル化、他の共有結合ヒストン修飾およびDNAメチルトランスフェラーゼによる染色体DNAのCpGアイランドでの直接メチル化を含む、クロマチン成分の別個の共有結合修飾の組合せ効果から生じるという証拠がかなりある。次に、それらの薬理学に影響を与える他の化合物と組み合わせて、PMT阻害剤の化合物A2を併用することの影響を、ヒストンデアセチラーゼ(HDAC)、ヒストンデメチラーゼ(HDM)、アセチルリジンリーダードメイン(ブロモドメイン)およびDNAメチルトランスフェラーゼ(DNMT)などの他のクロマチン修飾酵素の阻害によって試験した。これらの併用の結果を表4に要約し、MV4−11細胞の文脈において、いくつかのHDAC阻害剤との拮抗作用から相乗作用までの一連の効果を示す。これらの他のクロマチン修飾酵素阻害剤の中で、化合物A2と併用した場合、DNMT阻害剤デシタビンおよびアザシチジンが、MLL再構成細胞において相乗的な抗増殖活性を示した。これに対して、また化合物A2の作用機序と一致して、非MLL再構成白血病細胞株SKM−1で試験した場合に、この化合物は、いずれのDNMT阻害剤の抗増殖性の活性にも影響を及ぼさなかった(表4)。図35に、MV4−11およびMOLM−13細胞株におけるアザシチジンと化合物A2との併用の強力な相乗効果に関する代表的なデータを示す。同様の相乗作用はまた、化合物A2を別のDNMT阻害剤デシタビンと併用した場合にも、これらの細胞株で観察された(表4)。
方法
MOLM−13細胞またはSKM−1細胞は、4日間の前処理期間の間、T175フラスコ中で300nMのEPZ−5676(つまり化合物A2)またはDMSOにより前処理した。細胞は、EPZ−5676またはDMSO含有成長培地を使用して分割し、さらなる3日間の前処理期間の間、さらにインキュベートした。細胞は、最終的に、500細胞/ウェルの密度で、384ウェルプレート中EPZ−5676またはDMSOを含有する成長培地中に接種した。次いで、細胞は、第2の化合物による治療の前に24時間、インキュベーターにおいて平衡化した。治療したアッセイプレートを、72時間、第2の化合物と共にインキュベートした。この期間の後、プレートは、細胞生存率の指標として使用されるATP含量を測定するためのATPLiteを使用してエンドポイントでの分析のために現像した。
方法
最初のスクリーニングのために、MOLM−13細胞、OCI−AML−4細胞、ML−2細胞、THP−1細胞、RS4−11細胞、またはSKM−1細胞は、4日間の前処理期間の間、T175フラスコ中で300nMのEPZ−5676(つまりピノメトスタットもしくは化合物A2)またはDMSOにより前処理した。細胞は、EPZ−5676またはDMSO含有成長培地を使用して分割し、さらなる3日間の前処理期間の間、さらにインキュベートした。細胞は、最終的に、500細胞/ウェルの密度で、384ウェルプレート中EPZ−5676またはDMSOを含有する成長培地中に接種した。次いで、細胞は、第2の化合物による治療の前に24時間、インキュベーターにおいて平衡化した。治療したアッセイプレートを、72時間、第2の化合物と共にインキュベートした。この期間の後、プレートは、細胞生存率の指標として使用されるATP含量を測定するためのATPLiteを使用してエンドポイントでの分析のために現像した。
式中、Tが被験物質についてのシグナル尺度であり、Vはビヒクル治療コントロール尺度であり、V0は0時間のビヒクルコントロール尺度である。
化合物A2および第2の治療剤(ロシグリタゾンまたはT0070907)は、実施例3、同時処理モデルなどのような前の実施例において開示される方法に従ってMOLM−13細胞に投与した。併用投与からの結果を、下記の表に列挙し、図36Aおよび36Bに示す。
Claims (95)
- 化合物A2および化合物D16のいずれか1つまたはその薬学的に許容される塩ならびに1つまたは複数の治療剤を含む併用。
- 化合物A2またはその薬学的に許容される塩および1つまたは複数の治療剤を含む併用。
- 化合物D16またはその薬学的に許容される塩および1つまたは複数の治療剤を含む併用。
- 前記1つまたは複数の治療剤が、抗癌剤である、請求項1〜3のいずれか一項に記載の併用。
- 前記1つまたは複数の治療剤が、Ara−C、ダウノルビシン、アザシチジン、デシタビン、パノビノスタット、ビダーザ、ミトキサントロン、メトトレキセート、マホスファミド、プレドニゾロン、ビンクリスチン、レナリドミド、ヒドロキシ尿素、Menin−MLL阻害剤MI−2、JQ1、IBET151、ボリノスタット、キザルチニブ、ミドスタウリン、トラニルシプロミン、LSD1阻害剤II、ナビトクラックス、ベルケイド、SRT−1720、フラゾリドン、フルダラビン、メルカプトプリン、オバトクラックス、ABT−199、トラメチニブ、クロファラビン、イブルチニブ、パルボシクリブ、AZ20、MK2206、BEZ235、T0070907、ロミデプシン、ティピファニブ、ボラセルチブ、化合物E10、10−ヒドロキシカンプトテシン、ABT−737、アリトレチノイン、AT7867、オウラノフィン、AZD8055、AZD6244、バリシチニブ、BEP800、ベキサロテン、BIX01294、硫酸ブレオマイシン、BMN673、BMS345541、BMS−754807、BX−912、C646、CAL−101、CAPE、セリバスタチンナトリウム、クロラムブチル、シスプラチン、CPI−203、ダブラフェニブ、GSK−LSD1、エルロチニブ塩酸塩、エトポシド、エベロリムス、ホスタマチニブジナトリウム、GDC−0941、Go 6976、GSK2656157、IKK−2阻害剤VIII、イリノテカン塩酸塩、JNJ26854165、KU0063794、ラパチニブ、LB42708、LDN57444、LEE011、LY2603618、メルファラン、メナジオン、メチルプレドニソロン、マイトマイシンC、MK−2206、MLN2238、MS436、MS−275、NKH477、NU7441、ニュートリン−3、オラパリブ、OTX015、オキサリプラチン、パパベリン塩酸塩、パルテノライド、PHA−793887、ポマリドミド、ラロキシフェン塩酸塩、SB−505124、SCH772984、SGC−CBP30、SMER3、ソラフェニブ、SRT1720、TANSHINONE IIA、テムシロリムス、チオストレプトン、チオテパ、トポテカン塩酸塩、トレチノイン、トリシリビン、UNC0646、VE−821、XL147、およびそのアナログ、誘導体、または併用から選択される、請求項1〜3のいずれか一項に記載の併用。
- 前記1つまたは複数の治療剤が、Ara−C、ダウノルビシン、デシタビン、ビダーザ、ミトキサントロン、JQ1、IBET151、パノビノスタット、ボリノスタット、キザルチニブ、ミドスタウリン、トラニルシプロミン、LSD1阻害物質II、ナビトクラックス、およびそれらのアナログ、誘導体または併用から選択される、請求項1〜3のいずれか一項に記載の併用。
- 前記治療剤が、Ara−C、ダウノルビシン、ビダーザ、PPARアンタゴニスト、またはそのアナログもしくは誘導体である、請求項1〜3のいずれか一項に記載の併用。
- 前記治療剤が、Ara−C、ダウノルビシン、またはそのアナログもしくは誘導体である、請求項1〜3のいずれか一項に記載の併用。
- 前記治療剤が、ビダーザまたはそのアナログもしくは誘導体である、請求項1〜3のいずれか一項に記載の併用。
- 前記治療剤が、MEK1阻害剤、MEK2阻害剤、ERK阻害剤、RAF阻害剤、またはRAS阻害剤である、請求項1〜3のいずれか一項に記載の併用。
- 前記治療剤が、トラメチニブまたはそのアナログもしくは誘導体である、請求項1〜3のいずれか一項に記載の併用。
- 治療有効量の請求項1〜11のいずれか一項の併用および薬学的に許容されるキャリアを含む医薬組成物。
- 疾患の症状を治療するまたは緩和するための方法であって、それを必要とする被検体に、治療有効量の請求項1〜11のいずれかの併用を投与することを含む方法。
- 前記疾患が癌または前癌性状態である、請求項13に記載の方法。
- 前記疾患が、ヒストンまたは他のタンパク質のメチル化状態の調節により影響を受けることがある、請求項13に記載の方法。
- 前記メチル化状態が、DOT1Lの活性により少なくとも部分的に媒介される、請求項15に記載の方法。
- 癌の症状を治療するまたは緩和するための方法であって、それを必要とする被検体に、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される治療有効用量の化合物ならびに1つまたは複数の治療剤を投与するステップを含み、前記化合物および前記1つまたは複数の治療剤が、同時にまたは逐次的に投与される方法。
- 前記化合物が、前記1つまたは複数の治療剤の投与前に投与される、請求項17に記載の方法。
- 癌の症状を治療するまたは緩和するための方法であって、請求項1〜11のいずれかの併用の治療有効用量を投与する前に、それを必要とする被検体に、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される治療有効用量の化合物を投与するステップを含む方法。
- 請求項1に記載の併用が、1日当たり0.01mg/kg〜1日当たり約1000mg/kgの投薬量でそれを必要とする被験体に投与される、請求項13または19に記載の方法。
- 前記化合物が、1日当たり0.01mg/kg〜1日当たり約1000mg/kgの投薬量で投与される、請求項17または19に記載の方法。
- 前記1つまたは複数の治療剤が各々、1日当たり0.01mg/kg〜1日当たり約1000mg/kgの投薬量で投与される、請求項17または19に記載の方法。
- 前記化合物が、少なくとも36、45、54、70、80、または90mg/m2/日の用量で投与される、請求項17または19に記載の方法。
- 前記化合物が、少なくとも54mg/m2/日の用量で投与される、請求項17または19に記載の方法。
- 前記化合物が、少なくとも80mg/m2/日の用量で投与される、請求項17または19に記載の方法。
- 前記化合物が、少なくとも7、14、21、28、35、42、47、56、または64日間継続的に投与される、請求項17、19、または21〜25のいずれか一項に記載の方法。
- 継続投与が休薬日のない投与を含む、請求項26に記載の方法。
- 前記投与が白血病性芽球細胞の成熟または分化をもたらす、請求項13〜27のいずれか一項に記載の方法。
- 白血病性芽球細胞の少なくとも20%が成熟または分化する、請求項28に記載の方法。
- 白血病性芽球細胞の少なくとも50%が成熟または分化する、請求項28に記載の方法。
- 白血病性芽球細胞の少なくとも80%が成熟または分化する、請求項28に記載の方法。
- 投与が、無治療対照レベルの少なくとも90%、80%、70%、60%、50%、40%、30%、20%、10%またはそれ以下にH3K79メチルマークの低下をもたらす、請求項13〜31のいずれか一項に記載の方法。
- 投与が、H3K79メチルマークのリバウントの抑制をもたらす、請求項13〜32のいずれか一項に記載の方法。
- 投与が、白血病性芽球細胞の少なくとも20%、30%、40%、50%、60%、70%、80%または90%に細胞死またはアポトーシスをもたらす、請求項13〜33のいずれか一項に記載の方法。
- 前記治療方法が、発熱の消散、悪液質の消散または皮膚白血病の消散を含む、請求項13〜34のいずれか一項に記載の方法。
- 前記治療方法が、正常な造血の回復を含む、請求項13〜35のいずれか一項に記載の方法。
- 前記被検体が、請求項1〜11のいずれかの併用の成分のいずれか1つに対して、単剤として投与された場合に耐性を示す、請求項13〜36のいずれか一項に記載の方法。
- 前記被検体が、RAS−RAF−MEK−ERK経路において突然変異を有する、請求項13〜37のいずれか一項に記載の方法。
- 前記RAS−RAF−MEK−ERK経路における前記突然変異が、前記RAS−RAF−MEK−ERK経路のアップレギュレーションをもたらす、請求項13〜38のいずれか一項に記載の方法。
- 前記被検体が、前記RAS−RAF−MEK−ERK経路において活性化突然変異を有する、請求項13〜38のいずれか一項に記載の方法。
- 前記被検体が、3か月齢〜18歳の小児患者である、請求項13〜40のいずれか一項に記載の方法。
- 癌細胞増殖を阻害する方法であって、請求項1〜11のいずれかの併用と癌細胞を接触させるステップを含む方法。
- 癌細胞増殖を阻害するための方法であって、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される化合物ならびに1つまたは複数の治療剤と癌細胞を接触させるステップを含み、前記化合物および前記治療剤が、同時にまたは逐次的に送達される方法。
- 前記化合物が、前記1つまたは複数の治療剤の投与前に投与される、請求項43に記載の方法。
- 癌細胞増殖を阻害するための方法であって、請求項1〜11のいずれかの併用の治療有効用量を投与する前に、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される治療有効用量の化合物を投与するステップを含む方法。
- 前記治療剤が、Ara−C、ダウノルビシン、ビダーザまたはそれらのアナログもしくは誘導体である、請求項13〜45のいずれか一項に記載の方法。
- 前記被検体が白血病である、請求項13〜45のいずれか一項に記載の方法。
- 前記白血病が染色体再構成を特徴とする、請求項47に記載の方法。
- 前記染色体再構成が、混合系統白血病遺伝子(MLL)のキメラ融合またはMLLの縦列部分重複(MLL−PTD)である、請求項48に記載の方法。
- 前記被検体が、増加したレベルのHOXA9、Fms様チロシンキナーゼ3(FLT3)、MEIS1および/またはDOT1Lを有する、請求項13〜49のいずれか一項に記載の方法。
- 前記化合物が、化合物A2またはその薬学的に許容される塩である、請求項13〜50のいずれか一項に記載の方法。
- 前記化合物が、化合物D16またはその薬学的に許容される塩である、請求項13〜50のいずれか一項に記載の方法。
- 疾患の症状を治療するまたは緩和するための方法であって、それを必要とする被検体に、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される治療有効量の化合物を投与するステップを含み、前記治療有効量は、治療剤によるその後の治療に対して前記被検体を感作するのに十分な量である方法。
- 前記感作された被検体に治療有効量の治療剤を投与することをさらに含む、請求項53に記載の方法。
- 前記治療剤が、Ara−C、ダウノルビシン、ビダーザまたはそれらのアナログもしくは誘導体である、請求項53または54に記載の方法。
- 前記被検体が白血病である、請求項53〜55のいずれか一項に記載の方法。
- 前記白血病が染色体再構成を特徴とする、請求項56に記載の方法。
- 前記染色体再構成が、混合系統白血病遺伝子(MLL)のキメラ融合またはMLLの縦列部分重複(MLL−PTD)である、請求項57に記載の方法。
- 前記被検体が、増加したレベルのHOXA9、Fms様チロシンキナーゼ3(FLT3)、MEIS1および/またはDOT1Lを有する、請求項53〜58のいずれか一項に記載の方法。
- 前記化合物が、化合物A2またはその薬学的に許容される塩である、請求項53〜59のいずれか一項に記載の方法。
- 前記化合物が、化合物D16またはその薬学的に許容される塩である、請求項53〜59のいずれか一項に記載の方法。
- 前記治療剤が、標準治療薬である、請求項53〜61のいずれか一項に記載の方法。
- 前記治療剤が、前記化合物の投与後少なくとも1時間、2時間、3時間、またはそれ以上で投与される、請求項53〜62のいずれか一項に記載の方法。
- 前記治療剤が、前記化合物の投与後少なくとも1日、2日、3日、またはそれ以上で投与される、請求項53〜63のいずれか一項に記載の方法。
- 前記感作が、ヒストンまたは他のタンパク質のメチル化状態により判定される、請求項53〜64のいずれか一項に記載の方法。
- 前記感作が、ヒストンまたは他のタンパク質のメチル化レベルの低下により判定され、前記レベルは、感作されていない被検体と比較して低下している、請求項53〜64のいずれか一項に記載の方法。
- 前記感作が、H3K79のメチル化レベルの低下により判定される、請求項53〜64のいずれか一項に記載の方法。
- 治療的に有効である前記治療剤の量が、前記化合物により感作されなかった被検体における治療的に有効な前記治療剤の量よりも少ない、請求項53〜64のいずれか一項に記載の方法。
- 癌の症状を治療するまたは緩和するための方法であって、それを必要とする被検体に、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される治療有効用量の化合物ならびに1つまたは複数の治療剤を投与するステップを含み、前記1つまたは複数の治療剤が、前記化合物の投与前に投与される方法。
- 癌の症状を治療するまたは緩和するための方法であって、請求項1〜11のいずれかの併用の治療有効用量を投与する前に、それを必要とする被検体に、治療有効用量の1つまたは複数の治療剤を投与するステップを含む方法。
- 癌細胞増殖を阻害するための方法であって、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される化合物ならびに1つまたは複数の治療剤と癌細胞を接触させるステップを含み、前記1つまたは複数の治療剤が、前記化合物の投与前に投与される方法。
- 癌細胞増殖を阻害するための方法であって、請求項1〜11のいずれかの併用の治療有効用量を投与する前に、治療有効用量の1つまたは複数の治療剤を投与するステップを含む方法。
- 疾患の症状を治療するまたは緩和するための方法であって、それを必要とする被検体に、治療有効量の1つまたは複数の治療剤を投与するステップを含み、前記治療有効量が、化合物A2、化合物D16、およびその薬学的に許容される塩から選択される化合物または請求項1〜11のいずれかの併用によるその後の治療に対して前記被検体を感作するのに十分な量である方法。
- 前記治療剤が、Ara−Cである、請求項69〜73のいずれか一項に記載の方法。
- 前記化合物が、少なくとも36、45、54、70、80、または90mg/m2/日の用量で投与される、請求項69〜73のいずれか一項に記載の方法。
- 前記化合物が、少なくとも54mg/m2/日の用量で投与される、請求項69〜73のいずれか一項に記載の方法。
- 前記化合物が、少なくとも80mg/m2/日の用量で投与される、請求項69〜73のいずれか一項に記載の方法。
- 前記化合物が、少なくとも7、14、21、28、35、42、47、56、または64日間継続的に投与される、請求項69〜73のいずれか一項に記載の方法。
- 継続投与が休薬日のない投与を含む、請求項78に記載の方法。
- 前記投与が、白血病性芽球細胞の成熟または分化をもたらす、請求項69〜73のいずれか一項に記載の方法。
- 白血病性芽球細胞の少なくとも20%が成熟または分化する、請求項80に記載の方法。
- 白血病性芽球細胞の少なくとも50%が成熟または分化する、請求項80に記載の方法。
- 白血病性芽球細胞の少なくとも80%が成熟または分化する、請求項80に記載の方法。
- 投与が、無治療対照レベルの少なくとも90%、80%、70%、60%、50%、40%、30%、20%、10%またはそれ以下にH3K79メチルマークの低下をもたらす、請求項69〜73のいずれか一項に記載の方法。
- 投与が、H3K79メチルマークのリバウントの抑制をもたらす、請求項69〜73のいずれか一項に記載の方法。
- 投与が、白血病性芽球細胞の少なくとも20%、30%、40%、50%、60%、70%、80%または90%に細胞死またはアポトーシスをもたらす、請求項69〜73のいずれか一項に記載の方法。
- 前記治療方法が、発熱の消散、悪液質の消散または皮膚白血病の消散を含む、請求項69〜73のいずれか一項に記載の方法。
- 前記治療方法が、正常な造血の回復を含む、請求項69〜73のいずれか一項に記載の方法。
- 前記被検体が、請求項1〜11のいずれかの併用の成分のいずれか1つに対して、単剤として投与された場合に耐性を示す、請求項69〜73のいずれか一項に記載の方法。
- 前記被検体が、RAS−RAF−MEK−ERK経路において突然変異を有する、請求項69〜73および89のいずれか一項に記載の方法。
- 前記RAS−RAF−MEK−ERK経路における前記突然変異が、前記RAS−RAF−MEK−ERK経路のアップレギュレーションをもたらす、請求項69〜73および89〜90のいずれか一項に記載の方法。
- 前記被検体が、前記RAS−RAF−MEK−ERK経路において活性化突然変異を有する、請求項69〜73および89〜90のいずれか一項に記載の方法。
- 前記被検体が、3か月齢〜18歳の小児患者である、請求項69〜73および89〜92のいずれか一項に記載の方法。
- 前記化合物が、化合物A2またはその薬学的に許容される塩である、請求項69〜73および89〜93のいずれか一項に記載の方法。
- 前記化合物が、化合物D16またはその薬学的に許容される塩である、請求項69〜73および89〜93のいずれか一項に記載の方法。
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2015
- 2015-08-12 JP JP2017514624A patent/JP2017532312A/ja active Pending
- 2015-08-12 US US15/512,527 patent/US20190083521A1/en not_active Abandoned
- 2015-08-12 WO PCT/US2015/044907 patent/WO2016043874A2/en active Application Filing
- 2015-08-12 EP EP15842970.4A patent/EP3193884A4/en not_active Withdrawn
- 2015-08-12 CA CA2958847A patent/CA2958847A1/en not_active Abandoned
- 2015-08-12 AU AU2015318593A patent/AU2015318593A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP3193884A4 (en) | 2018-06-20 |
WO2016043874A2 (en) | 2016-03-24 |
US20190083521A1 (en) | 2019-03-21 |
WO2016043874A3 (en) | 2016-07-21 |
CA2958847A1 (en) | 2016-03-24 |
AU2015318593A1 (en) | 2017-02-23 |
EP3193884A2 (en) | 2017-07-26 |
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