JP2019532937A - Rnaポリメラーゼi阻害に基づく、がんの併用治療戦略 - Google Patents
Rnaポリメラーゼi阻害に基づく、がんの併用治療戦略 Download PDFInfo
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- JP2019532937A JP2019532937A JP2019515930A JP2019515930A JP2019532937A JP 2019532937 A JP2019532937 A JP 2019532937A JP 2019515930 A JP2019515930 A JP 2019515930A JP 2019515930 A JP2019515930 A JP 2019515930A JP 2019532937 A JP2019532937 A JP 2019532937A
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Abstract
Description
本発明は、米国国立衛生研究所(the National Institutes of Health)による助成金第 R21 CA193637-01 号の下で米国政府の支援を受けてなされた。前記政府は本発明において一定の権利を有する。
式中、X は NR2 であり;
式中、L は R3 又は任意選択的に置換されたシクロアミン
式中、R1 は直鎖又は分枝鎖の C1-C6 炭化水素基(例えば、アルキル基、アルケニル基、アルキニル基、アルキロール基、ヒドロキシアルキル基、アルコキシ基、アルコキシアルキル基、置換又は非置換のいずれでも、シクロペンチル、シクロヘキシル、ピラミド(pyramido)、フェニル若しくはベンジル、シクロアルキル、ヘテロシクリル、インドール等の環状基であり、ここで、アルキル、アリール、又はヘテロシクリル部分のそれぞれは、非置換、又はハロ、ヒドロキシ、カルボキシ、ホスホリル、ホスホニル、ホスホノ C1-C6 アルキル、カルボキシ C1-C6 アルキル、ジカルボキシ C1-C6 アルキル、ジカルボキシ・ハロ C1-C6 アルキル、スルホニル、シアノ、ニトロ、アルコキシ、アルキルチオ、アシル、アシルオキシ、チオアシル、アシルチオ、アリールオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アリールアルキルアミノ、グアニジノ、アルデヒド、ウレイド、及びアミノカルボニル、分岐鎖又は直鎖のアルキルアミノ、ジアルキルアミノ、若しくはアルキル若しくはジアルキルアミノアルキル、又はチオアルキル、チオアルケニル、チオアルキニル、アリールオキシ、アシルオキシ、チオアシル、アミド、スルホンアミド、等からなる群から選択される 1 種以上の置換基で置換されていることがある)等であり;
X が NR2 であるとき、R2 は H 又は直鎖 C1-C6 アルキル基であり;
L が R3 であるとき、R3 は直鎖又は分岐の C2-C6 アルキル基であり;
Lが
であるとき、m=1-8、及び各 Y は (CH2)nY1 pから独立して選択され、ここで n=1-8、p=0-4 であり、n と p の合計は少なくとも 2 であり、各 Y1 は独立して NR4、O、S、又は P から選択され、式中、R4 は、R3 について上で定義された通りであり、及び X≠O であり;若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む組成物、を提供する。
(I);
式中、X は NR2 であり;
式中、L は R3 又は任意選択的に置換されたシクロアミン
式中、R1 は直鎖又は分枝鎖の C1-C6 炭化水素基(例えば、アルキル基、アルケニル基、アルキニル基、アルキロール基、ヒドロキシアルキル基、アルコキシ基、アルコキシアルキル基、置換又は非置換のいずれでも、シクロペンチル、シクロヘキシル、ピラミド(pyramido)、フェニル若しくはベンジル、シクロアルキル、ヘテロシクリル、インドール等の環状基であり、ここで、アルキル、アリール、又はヘテロシクリル部分のそれぞれは、非置換、又はハロ、ヒドロキシ、カルボキシ、ホスホリル、ホスホニル、ホスホノ C1-C6 アルキル、カルボキシ C1-C6 アルキル、ジカルボキシ C1-C6 アルキル、ジカルボキシ・ハロ C1-C6 アルキル、スルホニル、シアノ、ニトロ、アルコキシ、アルキルチオ、アシル、アシルオキシ、チオアシル、アシルチオ、アリールオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アリールアルキルアミノ、グアニジノ、アルデヒド、ウレイド、及びアミノカルボニル、分岐鎖又は直鎖のアルキルアミノ、ジアルキルアミノ、若しくはアルキル若しくはジアルキルアミノアルキル、又はチオアルキル、チオアルケニル、チオアルキニル、アリールオキシ、アシルオキシ、チオアシル、アミド、スルホンアミド、等からなる群から選択される 1 種以上の置換基で置換されていることがある)等であり;
X が NR2 であるとき、R2 は H 又は直鎖 C1-C6 アルキル基であり;
L が R3 であるとき、R3 は直鎖又は分岐の C2-C6 アルキル基であり;
Lが
であるとき、m=1-8、及び各 Y は (CH2)nY1 pから独立して選択され、ここで n=1-8、p=0-4 であり、n と p の合計は少なくとも 2 であり、各 Y1 は独立して NR4、O、S、又は P から選択され、式中、R4 は、R3 について上で定義された通りであり、及び X≠O であり;若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、薬学的に許容される担体、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む医薬組成物、を提供する。
式中、R1=H 及び R2=C1-C6アルキル(1 以上の C1-C4 アルキル、OH、NH2、NR3R4、シアノ、SO2R3、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール(イミダゾリル、イミダゾリジノニル、ピリジル、インドリル、オキサゾリル、チアゾリル、オキサジアゾリル等を含むがこれらに限定されない)、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換の窒素含有複素環(アゼチジン、ピロリジン、ピペリジン、ピペラジン、アザピン、モルホリノ等を含むがこれらに限定されない)、で置換されている);式中、R2 が少なくとも 1 種の NR3R4 基で置換されている場合、R3 及び R4 は、H、C1-C6 アルキル、及び C1-C4 アルコキシル・アルキル等を含む群から独立して選択され、少なくとも 1 つのキラル炭素を有する、若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む組成物、を提供する。
式中、R1=H 及び R2=C1-C6アルキル(1 以上の C1-C4 アルキル、OH、NH2、NR3R4、シアノ、SO2R3、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール(イミダゾリル、イミダゾリジノニル、ピリジル、インドリル、オキサゾリル、チアゾリル、オキサジアゾリル等を含むがこれらに限定されない)、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換の窒素含有複素環(アゼチジン、ピロリジン、ピペリジン、ピペラジン、アザピン、モルホリノ等を含むがこれらに限定されない)、で置換されている);式中、R2 が少なくとも 1 種の NR3R4 基で置換されている場合、R3 及び R4 は、H、C1-C6 アルキル、及び C1-C4 アルコキシル・アルキル等を含む群から独立して選択され、少なくとも 1 つのキラル炭素を有する、若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、薬学的に許容される担体、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む医薬組成物、を提供する。
(I);
式中、X は NR2 であり;
式中、L は R3 又は任意選択的に置換されたシクロアミン
式中、R1 は直鎖又は分枝鎖の C1-C6 炭化水素基(例えば、アルキル基、アルケニル基、アルキニル基、アルキロール基、ヒドロキシアルキル基、アルコキシ基、アルコキシアルキル基、置換又は非置換のいずれでも、シクロペンチル、シクロヘキシル、ピラミド(pyramido)、フェニル若しくはベンジル、シクロアルキル、ヘテロシクリル、インドール等の環状基であり、ここで、アルキル、アリール、又はヘテロシクリル部分のそれぞれは、非置換、又はハロ、ヒドロキシ、カルボキシ、ホスホリル、ホスホニル、ホスホノ C1-C6 アルキル、カルボキシ C1-C6 アルキル、ジカルボキシ C1-C6 アルキル、ジカルボキシ・ハロ C1-C6 アルキル、スルホニル、シアノ、ニトロ、アルコキシ、アルキルチオ、アシル、アシルオキシ、チオアシル、アシルチオ、アリールオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アリールアルキルアミノ、グアニジノ、アルデヒド、ウレイド、及びアミノカルボニル、分岐鎖又は直鎖のアルキルアミノ、ジアルキルアミノ、若しくはアルキル若しくはジアルキルアミノアルキル、又はチオアルキル、チオアルケニル、チオアルキニル、アリールオキシ、アシルオキシ、チオアシル、アミド、スルホンアミド、等からなる群から選択される 1 種以上の置換基で置換されていることがある)等であり;
X が NR2 であるとき、R2 は H 又は直鎖 C1-C6 アルキル基であり;
L が R3 であるとき、R3 は直鎖又は分岐の C2-C6 アルキル基であり;
Lが
であるとき、m=1-8、及び各 Y は (CH2)nY1 pから独立して選択され、ここで n=1-8、p=0-4 であり、n と p の合計は少なくとも 2 であり、各 Y1 は独立して NR4、O、S、又は P から選択され、式中、R4 は、R3 について上で定義された通りであり、及び X≠O であり;若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む組成物、を提供する。
式中、X は NR2 であり;
式中、L は R3 又は任意選択的に置換されたシクロアミン
式中、R1 は直鎖又は分枝鎖の C1-C6 炭化水素基(例えば、アルキル基、アルケニル基、アルキニル基、アルキロール基、ヒドロキシアルキル基、アルコキシ基、アルコキシアルキル基、置換又は非置換のいずれでも、シクロペンチル、シクロヘキシル、ピラミド(pyramido)、フェニル若しくはベンジル、シクロアルキル、ヘテロシクリル、インドール等の環状基であり、ここで、アルキル、アリール、又はヘテロシクリル部分のそれぞれは、非置換、又はハロ、ヒドロキシ、カルボキシ、ホスホリル、ホスホニル、ホスホノ C1-C6 アルキル、カルボキシ C1-C6 アルキル、ジカルボキシ C1-C6 アルキル、ジカルボキシ・ハロ C1-C6 アルキル、スルホニル、シアノ、ニトロ、アルコキシ、アルキルチオ、アシル、アシルオキシ、チオアシル、アシルチオ、アリールオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アリールアルキルアミノ、グアニジノ、アルデヒド、ウレイド、及びアミノカルボニル、分岐鎖又は直鎖のアルキルアミノ、ジアルキルアミノ、若しくはアルキル若しくはジアルキルアミノアルキル、又はチオアルキル、チオアルケニル、チオアルキニル、アリールオキシ、アシルオキシ、チオアシル、アミド、スルホンアミド、等からなる群から選択される 1 種以上の置換基で置換されていることがある)等であり;
X が NR2 であるとき、R2 は H 又は直鎖 C1-C6 アルキル基であり;
L が R3 であるとき、R3 は直鎖又は分岐の C2-C6 アルキル基であり;
Lが
であるとき、m=1-8、及び各 Y は (CH2)nY1 pから独立して選択され、ここで n=1-8、p=0-4 であり、n と p の合計は少なくとも 2 であり、各 Y1 は独立して NR4、O、S、又は P から選択され、式中、R4 は、R3 について上で定義された通りであり、及び X≠O であり;若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、薬学的に許容される担体、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む医薬組成物、を提供する。
式中、R1=H 及び R2=C1-C6アルキル(1 以上の C1-C4 アルキル、OH、NH2、NR3R4、シアノ、SO2R3、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール(イミダゾリル、イミダゾリジノニル、ピリジル、インドリル、オキサゾリル、チアゾリル、オキサジアゾリル等を含むがこれらに限定されない)、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換の窒素含有複素環(アゼチジン、ピロリジン、ピペリジン、ピペラジン、アザピン、モルホリノ等を含むがこれらに限定されない)、で置換されている);式中、R2 が少なくとも 1 種の NR3R4 基で置換されている場合、R3 及び R4 は、H、C1-C6 アルキル、及び C1-C4 アルコキシル・アルキル等を含む群から独立して選択され、少なくとも 1 つのキラル炭素を有する、若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む組成物、を提供する。
式中、R1=H 及び R2=C1-C6アルキル(1 以上の C1-C4 アルキル、OH、NH2、NR3R4、シアノ、SO2R3、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール(イミダゾリル、イミダゾリジノニル、ピリジル、インドリル、オキサゾリル、チアゾリル、オキサジアゾリル等を含むがこれらに限定されない)、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換の窒素含有複素環(アゼチジン、ピロリジン、ピペリジン、ピペラジン、アザピン、モルホリノ等を含むがこれらに限定されない)、で置換されている);式中、R2 が少なくとも 1 種の NR3R4 基で置換されている場合、R3 及び R4 は、H、C1-C6 アルキル、及び C1-C4 アルコキシル・アルキル等を含む群から独立して選択され、少なくとも 1 つのキラル炭素を有する、若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、薬学的に許容される担体、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む医薬組成物、を提供する。
他の化学療法剤と併用した BMH-21 の効果。
本発明者らは、がん細胞の生存率について、化学療法剤のパネル(トポイソメラーゼ毒[ドキソルビシン、カンプトテシン、アクチノマイシン D、マイトマイシン C]、選択的 Pol I 阻害剤[CX-5461、BMH-9]、エピジェネティック・モジュレーター[5-アザ-2'-デオキシシチジン、トリコスタチン A]、ブドウ糖及びエネルギー代謝に影響を与える薬剤及び薬物[2-デオキシグルコース、ニコチンアミド]及びクロロキン(抗マラリア薬及びオートファジー阻害薬である)(Kimura et al., 2013))を使用して、BMH-21(Peltonen et al., 2014, Colis et al., 2014)の併用効果を試験した(図1)。前記薬物を一定濃度で混合し、がん細胞(A375 ヒト黒色腫細胞)に加え、48 時間インキュベートし、細胞生存率を Cell TiterBlue 生存率アッセイ(Promega)を使用して測定した。対照と比較した細胞死の割合を決定した。Chou-Talalay アルゴリズム(Chou 2010)を用いてデータを解析し、反復アッセイで、広範囲の効果レベルにわたって、相乗作用(CI <1)、拮抗作用(CI> 1)及び相加作用(CI~1)を示す薬物コンビネーション・インデックス(CI)を定義した。DNA 標的薬、いくつかの代謝阻害剤、他の選択的 Pol I 阻害剤及びエピジェネティック修飾剤は、BMH-21 と強い拮抗作用を示した(図1A‐D)。しかしながら、BMH-21 とクロロキンの併用は強い相乗作用を示した(図1E)。この相乗効果のより詳細な評価を以下に示す。
BMH-21 とオートファジー阻害剤の併用効果。
本発明者らは更に、BMH-21 と、オートファジー阻害剤であり、より一般的には抗マラリア薬として知られていて、医学的な経緯が広範に、且つ良く知られているクロロキン(CQ)との併用活性を試験した。MR49F エンザルタミド耐性前立腺がん細胞の生存率に関するそれらの併用活性を評価し、薬物相互作用について Chou-Talalay 解析を適用した。CQ 単独では、前立腺がん細胞の生存率に影響が無かった。BMH-21/CQ の併用は MR49F 細胞において相乗的であった(図2A)。図2B‐2Dに示すように、BMH-21 及び CQ の併用処置は、オートファジー阻害のマーカーである LC3-II の発現を増加させた。LC3 は、ウエスタン・ブロッティング及び免疫蛍光解析の両方によって検出されるように、MR49F 細胞における併用処置によって増加し、典型的な点状パターンで細胞質に存在した(図2C、2D)。この発見は、MR49F 細胞がオートファジー経路に依存していることを示している。エンザルタミド耐性細胞のオートファジー感受性は最近 Evans のグループによって提案された(Nguyen et al., 2014)が、ここで取り入れた併用戦略は新規である。我々は、Pol I の阻害が、リボソーム生合成の喪失、小胞体ストレス応答(unfolded protein response)、及び ER ストレスによって、タンパク質翻訳の減少をもたらし、それがオートファジー経路を活性化し、オートファジー経路は細胞生存に必要であると、仮定している。CX-5461 及びアクチノマイシン D で処理した細胞においてオートファジー・マーカーのレベルが上昇することは、これまでの 2 つの報告で観察されているが(Drygin et al., 2011; Katagiri et al., 2015)、Pol I の阻害を、オートファジー阻害と併用する治療戦略の恩恵の可能性に関して、試験したり、結びつけた報告は全く無い。
BMH-21 と ACAT1 阻害剤の併用効果。
いくつかの研究によれば、脂質代謝の変化が、がん細胞のサインであることが示唆されてきている。コレステロールが膜脂質の主要なビルディング・ブロック(building block)であり。及びステロイド系ホルモンの原料であることを考えると、この考察は、前立腺がん、乳がん、肝臓がん及び膵臓がんに特に関係があり、他のあらゆるがんにも関係がある。脂質滴(lipid droplets)は、ER に由来する脂質貯蔵オルガネラである。細胞に対して毒性である遊離コレステロールは、アシルコエンザイム A:コレステロール・アシルトランスフェラーゼ(acyl coenzyme A:cholesterol acyltransferase(ACAT1 、SOAT1 によってコードされる))によってコレステリル・エステルに変換され、そして脂肪滴(lipid droplets)に貯蔵される(Ikonen et al., 2008; Chang et al., 2009)。
BMH-21 と PARP 阻害剤の併用効果。
ポリ(ADP)リボース・ポリメラーゼ(PARP)は、しばしば細胞ストレス後(最も顕著には遺伝毒性ストレス後)すぐに、タンパク質の可逆的修飾(PARylation)を引き起こす酵素である(Lord and Ashworth 2013)。PARPs の臨床的な阻害剤は、DNA 損傷の修復を損なうことによって、及び転写の調節によって作用すると推定される(Feng et al., 2015)。PARP 阻害剤は、BRCA1 及び BRCA2 等の相同組換えによる DNA 損傷修復に必要な遺伝子の遺伝的欠陥を有する腫瘍において有効であることが特に見出されてきている。多数の文献が、転写抑制因子としての PARP の役割を実証している(Feng et al., 2015)。PARP1 及び PARP2 の両方は核に局在する(DNA 損傷に対する応答因子及び転写調節因子としてのそれらの役割と一致する)が、両方とも核小体においても観察されている。PARP1 は、サイレントな(silent)リボソーム DNA 遺伝子に結合し、そして rDNA サイレンシング(rDNA silencing)を増加させることが報告されている(Guetg et al., 2012)。PARP1 が枯渇することによって、また、Pol I による転写が増加することも報告されてきている(Guetg et al., 2012)。しかしながら、PARP 及び Pol I による転写の両方を標的とすることによるがん治療戦略を示唆する提案又は根拠は以前にはない。
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Claims (11)
- 式Iの化合物:
式中、X は NR2 であり;
式中、L は R3 又は任意選択的に置換されたシクロアミン
であり;
式中、R1 は直鎖又は分枝鎖の C1-C6 炭化水素基(例えば、アルキル基、アルケニル基、アルキニル基、アルキロール基、ヒドロキシアルキル基、アルコキシ基、アルコキシアルキル基、置換又は非置換のいずれでも、シクロペンチル、シクロヘキシル、ピラミド(pyramido)、フェニル若しくはベンジル、シクロアルキル、ヘテロシクリル、インドール等の環状基であり、ここで、アルキル、アリール、又はヘテロシクリル部分のそれぞれは、非置換、又はハロ、ヒドロキシ、カルボキシ、ホスホリル、ホスホニル、ホスホノ C1-C6 アルキル、カルボキシ C1-C6 アルキル、ジカルボキシ C1-C6 アルキル、ジカルボキシ・ハロ C1-C6 アルキル、スルホニル、シアノ、ニトロ、アルコキシ、アルキルチオ、アシル、アシルオキシ、チオアシル、アシルチオ、アリールオキシ、アミノ、アルキルアミノ、ジアルキルアミノ、トリアルキルアミノ、アリールアルキルアミノ、グアニジノ、アルデヒド、ウレイド、及びアミノカルボニル、分岐鎖又は直鎖のアルキルアミノ、ジアルキルアミノ、若しくはアルキル若しくはジアルキルアミノアルキル、又はチオアルキル、チオアルケニル、チオアルキニル、アリールオキシ、アシルオキシ、チオアシル、アミド、スルホンアミド、等からなる群から選択される 1 種以上の置換基で置換されていることがある)等であり;
X が NR2 であるとき、R2 は H 又は直鎖 C1-C6 アルキル基であり;
L が R3 であるとき、R3 は直鎖又は分岐の C2-C6 アルキル基であり;
Lが
であるとき、m=1-8、及び各 Y は (CH2)nY1 pから独立して選択され、ここで n=1-8、p=0-4 であり、n と p の合計は少なくとも 2 であり、各 Y1 は独立して NR4、O、S、又は P から選択され、式中、R4 は、R3 について上で定義された通りであり、及び X≠O であり;若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む組成物。 - 式IIの化合物、
(II)、
式中、R1=H 及び R2=C1-C6アルキル(1 以上の C1-C4 アルキル、OH、NH2、NR3R4、シアノ、SO2R3、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール(イミダゾリル、イミダゾリジノニル、ピリジル、インドリル、オキサゾリル、チアゾリル、オキサジアゾリル等を含むがこれらに限定されない)、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換の窒素含有複素環(アゼチジン、ピロリジン、ピペリジン、ピペラジン、アザピン、モルホリノ等を含むがこれらに限定されない)、で置換されている);式中、R2 が少なくとも 1 種の NR3R4 基で置換されている場合、R3 及び R4 は、H、C1-C6 アルキル、及び C1-C4 アルコキシル・アルキル等を含む群から独立して選択され、少なくとも 1 つのキラル炭素を有する、若しくは薬学的に許容される塩、溶媒和物、立体異性体、又はそれらのプロドラッグ、並びに有効量の少なくとも 1 種以上の以下:オートファジー阻害化合物;ACAT1 阻害化合物;及び PARP 阻害化合物からなる群から選択される化合物、を含む組成物。 - 以下:
- 前記オートファジー阻害化合物が:クロロキン、ヒドロキシクロロキン、リソソーム内腔アルカリ化剤、Lys01、Lys05 及びそれらの二量体型のヒドロキシクロロキン(ビスアミノキノリン)、バフィロマイシン A1、液胞型 H(+)-ATPases(V-ATPases)((3Z,5E,7R,8S,9S,11E,13E,15S,16R)-16-[(2S,3R,4S)-4-[(2R,4R,5S,6R)-2,4-ジヒドロキシ-5-メチル-6-プロパン-2-イルオキサン-2-イル]-3-ヒドロキシペンタン-2-イル]-8-ヒドロキシ-3,15-ジメトキシ-5,7,9,11-テトラメチル-1-オキサシクロヘキサデカ-3,5,11,13-テトラエン-2-オン)、スパウチン-1(Spautin-1)(6-フルオロ-N-[4-フルオロベンジル]キナゾリン-4-アミン) 及び誘導体、ユビキチン・ペプチダーゼ及びオートファジーの阻害剤、SBI-0206965(2-(5-ブロモ-2-(3,4,5-トリメトキシフェニルアミノ)ピリミジン-4-イルオキシ)-N-メチルベンズアミド)、ULK1 阻害剤、DBeQ(N2,N4-ジベンジルキナゾリン-2,4-ジアミン)、選択的 p97ATPase 阻害剤;オートファゴソーム成熟を遮断する、E 64d((2S,3S)-トランス-エポキシスクシニル-L-ロイシルアミド-3-メチルブタン・エチル・エステル)、カテプシン阻害剤;オートリソソームでの消化を妨害する、及び ML240(2-(2-アミノ-1H-ベンゾ[d] イミダゾール-1-イル)-N-ベンジル-8-メトキシキナゾリン-4-アミン)、並びにそれらの誘導体、からなる群から選択される、請求項1から3の何れか一項に記載の組成物。
- 前記 ACAT1 阻害化合物が:アバシミベ(Avasimibe)(CI-1011)、アバシミン ATR-101(PD132301-2、N-[2,6-ビス(1-メチルエチル)-フェニル]-N’-[[1-[4-(ジメチル-アミノ)フェニル]シクロペンチル]メチル]尿素)、パクチミベ(Pactimibe)(CS-505)2-[7-(2,2-ジメチルプロパノイルアミノ)-4,6-ジメチル-1-オクチル-2,3-ジヒドロインドール-5-イル]酢酸、K-604(2-[4-[2-(ベンズイミダゾール-2-イルチオ)エチル]ピペラジン-1イル]-N-[2,4-ビス(メチルチオ)-6-メチル-3-ピリジル]アセトアミド)、リモナバント(5-(4-クロロフェニル)-1-(2,4-ジクロロ-フェニル)-4-メチル-N-(ピペリジン-1-イル)-1H-ピラゾール-3-カルボキサミド)、ボーベリオライド(Beauveriolide)、NBV274、285 及び 300、F12511(エフルシミベ(eflucimibe、(2S)-2-ドデシルスルファニル-N-(4-ヒドロキシ-2,3,5-トリメチルフェニル)-2-フェニルアセトアミド)、CL-283,546(N'-ヘプチル-N-((4-(3-メチルブチル) フェニル)メチル)-N'-(2,4,6-トリフルオロフェニル)尿素)、及び F-1394((1s,2s)-2-[3-(2,2-ジメチルプロピル)-3-ノニルウレイド] アミノシクロヘキサン-1-イル 3-[N-(2,2,5,5-テトラメチル-1,3-ジオキサン-4-カルボニル)アミノ] プロピオネート)、又はそれらの誘導体、からなる群から選択される、請求項1から3の何れか一項に記載の組成物。
- 前記 PARP 阻害化合物が:オラパリブ(olaparib)(AZD2811)4-[[3-[4-(シクロプロパンカルボニル) ピペラジン-1-カルボニル]-4-フルオロフェニル]メチル]-2H-フタラジン-1-オン、ベリパリブ(veliparib)(ABT888) 2-[(2R)-2-メチルピロリジン-2-イル]-1H-ベンズイミダゾール-4-カルボキサミド、ルカパリブ(rucaparib)(AG014699)、ニラパリブ(niraparib)(MK4827)2-[4-[(3S)- ピペリジン-3-イル]フェニル] インダゾール-7-カルボキサミド、タラゾパリブ(talazoparib)(BMN673)8S,9R)-5-フルオロ-8-(4-フルオロフェニル)-9-(1-メチル-1H-1,2,4-トリアゾール-5-イル)-8,9-ジヒドロ-2H-ピリド[4,3,2-デ] フタラジン-3(7H)-オン、CEP-9722 及び CEP-8983、並びに MRL-45696(ニラパリブ誘導体(niraparib derivative))、又はそれらの誘導体、からなる群から選択される、請求項1から3の何れか一項に記載の組成物。
- 請求項1から6の何れか一項に記載の組成物と薬学的に許容される担体とを含む医薬組成物。
- 有効量の少なくとも 1 種の追加の治療剤又は化学療法剤を更に含む、請求項1から7の何れか一項に記載の組成物又は医薬組成物。
- 腫瘍性疾患を患っている対象における腫瘍性疾患に化学療法剤としての使用をするための、請求項1から8の何れか一項に記載の組成物又は医薬組成物。
- 前記腫瘍性疾患が腫瘍である、請求項9に記載の使用をするための、組成物又は医薬組成物。
- 前記腫瘍が、乳がん、前立腺がん、膵臓がん、大腸がん、肝臓がん、膠芽細胞腫、卵巣がん、白血病、ホジキン・リンパ腫及び多発性骨髄腫由来である、請求項10に記載の使用をするための、組成物又は医薬組成物。
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AU2017330390A1 (en) | 2019-04-18 |
CA3037928A1 (en) | 2018-03-29 |
EP3515448A4 (en) | 2020-04-08 |
US20190247397A1 (en) | 2019-08-15 |
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