JP2017533222A - スーパーエンハンサー領域において転写制御を標的とする方法 - Google Patents
スーパーエンハンサー領域において転写制御を標的とする方法 Download PDFInfo
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- JP2017533222A JP2017533222A JP2017523502A JP2017523502A JP2017533222A JP 2017533222 A JP2017533222 A JP 2017533222A JP 2017523502 A JP2017523502 A JP 2017523502A JP 2017523502 A JP2017523502 A JP 2017523502A JP 2017533222 A JP2017533222 A JP 2017533222A
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- arbocidib
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Abstract
Description
(技術分野)
本発明は、概して、スーパーエンハンサーにより調節される疾患を処置する方法および処置用の組成物を対象とする。
スーパーエンハンサーは、DNAの転写的に活性な領域の大型のクラスターであり、細胞の同一性を制御する遺伝子の発現を推進する。スーパーエンハンサーは、がんを含む、ただしこれに限定されない多重疾患症状においては調節不全に陥る。スーパーエンハンサーは、直鎖状のDNAにおいて必ずしも近傍に位置する必要のない複数の遺伝子の発現を同時に調節する大型の複合体を形成する転写因子、補助因子、クロマチン調節因子、シグナリング酵素(例えば、キナーゼ)、および転写装置(例えば、RNAポリメラーゼII)を補充する(SmithおよびShilatifard、2014年、Nature Structural and Molecular Biology、第21巻(3号):210〜219頁)。スーパーエンハンサーは、細胞が協働的に作用して細胞の同一性を決定または維持する遺伝子のグループを調節することにおいて能力を有することを可能にする。がん細胞は、がん細胞の転写活性が変化するようにスーパーエンハンサー複合体を再プログラムし、発がん、転移、および疾患進行に至ることが実証されている。実際、がんに限らず、多くの疾患が、スーパーエンハンサー複合体の異常に最終的に起因するものと仮定されている(Cell、2013年11月7日、第155巻(4号):934〜47頁)。
進歩しているとは言え、スーパーエンハンサーの標的化の改善、およびスーパーエンハンサーが媒介する疾患を処置する方法に対するニーズが当技術分野においてなおも残っている。本発明は、本ニーズを満たし、関連する利益を提供する。
端的には、本発明の実施形態は、スーパーエンハンサーの2つまたはそれ超の構成要素のインヒビターの投与を含む、疾患を処置する方法を提供する。一実施形態では、本開示は、それを必要とする哺乳動物において、スーパーエンハンサー媒介型疾患を処置する方法であって、下記の治療剤:
i)サイクリン依存性キナーゼインヒビター、
ii)ブロモドメインインヒビター、
iii)ヒストンメチルトランスフェラーゼインヒビター、
iv)ヒストンデアセチラーゼインヒビター、および
v)ヒストンデメチラーゼインヒビター
のうちの少なくとも2つの有効量を哺乳動物に投与するステップを含む、方法を提供する。
以下の説明では、ある特定の具体的詳細が、本発明の様々な実施形態の完全な理解を提供するために記載される。しかし、当業者は、本発明は、これらの詳細情報がなくても実践可能であることを理解し得る。
「処置する」または「処置」には、本明細書で使用する場合、目的の疾患または症状を有する哺乳動物、好ましくはヒトにおける目的の疾患または症状の処置が含まれ、
(i)疾患または症状が哺乳動物に生ずるのを、特にそのような哺乳動物が、その症状について易罹患性であるが、その症状を有するものとまだ診断されないときに予防すること、
(ii)疾患または症状を阻害する、すなわちその発症を阻止すること、
(iii)疾患または症状を緩和する、すなわち疾患または症状の後退を引き起こすこと、あるいは
(iv)疾患または症状に起因する徴候を緩和する、すなわち基礎疾患または症状に対処することなく疼痛を緩和すること、
を含む。
本明細書で使用する場合、用語「疾患」および「症状」は、交換可能に使用可能であり得るか、あるいは特定の病気または症状は、公知の原因因子を有さない(したがって、病因はまだ解明されていない)場合もあり、したがって、望ましくない症状または症候群として認識されているに過ぎず、疾患としていまだ認識されておらず、多少の特別な一連の徴候が臨床医により識別されているという点において異なる可能性がある。
I.方法
i)サイクリン依存性キナーゼインヒビター、
ii)ブロモドメインインヒビター、
iii)ヒストンメチルトランスフェラーゼインヒビター、
iv)ヒストンデアセチラーゼインヒビター、および
v)ヒストンデメチラーゼインヒビター、
のうちの少なくとも2つの有効量を哺乳動物に投与するステップを含む、方法を提供する。
II.医薬組成物
i)サイクリン依存性キナーゼインヒビター、
ii)ブロモドメインインヒビター、
iii)ヒストンメチルトランスフェラーゼインヒビター、
iv)ヒストンデアセチラーゼインヒビター、および
v)ヒストンデメチラーゼインヒビター
のうち少なくとも2つを含む。
腫瘍容積に対する併用治療の効果
(実施例2)
c−MYC発現に対する併用治療の効果
(実施例3)
IC50に対する併用治療の効果
アルボシジブによるMYCおよびMCL−1発現の阻害
アルボシジブのMYCおよびMCL−1阻害活性を決定するために、MV4−11細胞をアルボシジブで2時間処置し、HPRTと比較してMYCおよびMCL−1の発現を決定した。データは、アルボシジブは、単一の薬剤としてMV4−11細胞におけるMYC発現を完全に排除し(図5A)、MCL−1発現を60%低下させる(図5B)ことを示す。
(実施例5)
BRD4インヒビターと組み合わせたアルボシジブは、MV4−11細胞におけるアポトーシスを増加させる
(実施例6)
BRD4インヒビターと組み合わせたアルボシジブにより、MV4−11細胞におけるMYCおよびMCL−1発現が、個々の処置よりも良好に低下する
(実施例7)
アルボシジブは、時間および用量に依存してCDK9とHexim1タンパク質との会合を増加させる
(実施例8)
アルボシジブは、スーパーエンハンサー複合体調節型遺伝子を、時間および用量に依存して抑制する
(実施例9)
アルボシジブは、固形腫瘍および神経芽細胞腫細胞におけるタンパク質の発現を、時間に依存して抑制する
(実施例10)
アルボシジブは、MV4−11細胞におけるmRNA発現を時間に依存して抑制する
(実施例11)
JQ−1と組み合わせたアルボシジブは、個々の処置よりも良好に、A549細胞におけるMCL−1およびc−MYC発現を低減する
(実施例12)
JQ−1と組み合わせたアルボシジブは、A549細胞におけるアポトーシスを用量に依存して増加させる
(実施例13)
JQ−1組み合わせたジナシクリブは、A549細胞におけるアポトーシスを用量に依存して増加させる
(実施例14)
アルボシジブは、A549細胞におけるMCL−1およびc−MYC発現を低減する
(実施例15)
CDK9特異的siRNAをBETインヒビターと協同させると、A549細胞におけるタンパク質の発現は低減し、アポトーシスは増加する
Claims (30)
- それを必要とする哺乳動物において、スーパーエンハンサー媒介型疾患を処置する方法であって、下記の治療剤:
i)サイクリン依存性キナーゼインヒビター、
ii)ブロモドメインインヒビター、
iii)ヒストンメチルトランスフェラーゼインヒビター、
iv)ヒストンデアセチラーゼインヒビター、および
v)ヒストンデメチラーゼインヒビター、
のうちの少なくとも2つの有効量を前記哺乳動物に投与するステップを含む方法。 - 前記治療剤のうちの少なくとも1つが、サイクリン依存性キナーゼインヒビターである、請求項1に記載の方法。
- 前記サイクリン依存性キナーゼインヒビターが、Cdk7、Cdk9、または両方を阻害する、請求項2に記載の方法。
- 前記少なくとも1つの治療剤が、CDK9特異的siRNA、アルボシジブ、またはジナシクリブである、請求項2に記載の方法。
- 前記治療剤のうちの少なくとも1つが、ブロモドメインインヒビターである、請求項1から4のいずれか一項に記載の方法。
- 前記ブロモドメインインヒビターが、Brd4を阻害する、請求項5に記載の方法。
- 前記少なくとも1つの治療剤が、JQ−1、BI2536、TG101209、OTX015、IBET762、IBET151、CPI−0610、またはPFI−1である、請求項5または6のいずれか一項に記載の方法。
- 前記治療剤のうちの少なくとも1つが、ヒストンメチルトランスフェラーゼインヒビターである、請求項1から7のいずれか一項に記載の方法。
- 前記少なくとも1つの治療剤が、Dot1L阻害剤EPZ−5676である、請求項8に記載の方法。
- 前記治療剤のうちの少なくとも1つが、ヒストンデアセチラーゼインヒビターである、請求項1から9のいずれか一項に記載の方法。
- 前記少なくとも1つの治療剤が、パノビノスタットまたはSAHAである、請求項10に記載の方法。
- 前記治療剤が、ヒストンデメチラーゼインヒビターである、請求項1から11のいずれか一項に記載の方法。
- 前記少なくとも1つの治療剤が、HCI−2509である、請求項12に記載の方法。
- 有効量のサイクリン依存性キナーゼインヒビターおよびブロモドメインインヒビターを、前記哺乳動物に投与するステップを含む、請求項1に記載の方法。
- 前記サイクリン依存性キナーゼインヒビターが、CDK9特異的siRNAまたはアルボシジブである、請求項14に記載の方法。
- 前記ブロモドメインインヒビターが、JQ1である、請求項14または15のいずれか一項に記載の方法。
- 有効量のサイクリン依存性キナーゼインヒビターおよびヒストンデアセチラーゼインヒビターを、前記哺乳動物に投与するステップを含む、請求項1に記載の方法。
- 前記サイクリン依存性キナーゼインヒビターが、アルボシジブである、請求項17に記載の方法。
- 前記ヒストンデアセチラーゼインヒビターが、パノビノスタットである、請求項17または18のいずれか一項に記載の方法。
- 前記スーパーエンハンサー媒介型疾患が、がんである、請求項1から19のいずれか一項に記載の方法。
- 前記スーパーエンハンサー媒介型疾患が、急性骨髄性白血病である、請求項1から19のいずれか一項に記載の方法。
- 薬学的に許容される担体または賦形剤、ならびに下記の治療剤:
i)サイクリン依存性キナーゼインヒビター、
ii)ブロモドメインインヒビター、
iii)ヒストンメチルトランスフェラーゼインヒビター、
iv)ヒストンデアセチラーゼインヒビター、および
v)ヒストンデメチラーゼインヒビター、
のうちの少なくとも2つを含む医薬組成物。 - サイクリン依存性キナーゼインヒビターを含む、請求項22に記載の医薬組成物。
- 前記サイクリン依存性キナーゼインヒビターが、CDK9特異的siRNA、アルボシジブ、またはジナシクリブである、請求項23に記載の医薬組成物。
- サイクリン依存性キナーゼインヒビターおよびブロモドメインインヒビターを含む、請求項22に記載の医薬組成物。
- 前記サイクリン依存性キナーゼインヒビターが、CDK9特異的siRNAまたはアルボシジブである、請求項25に記載の医薬組成物。
- 前記ブロモドメインインヒビターが、JQ1である、請求項25または26のいずれか一項に記載の医薬組成物。
- サイクリン依存性キナーゼインヒビターおよびヒストンデアセチラーゼインヒビターを含む、請求項22に記載の医薬組成物。
- 前記サイクリン依存性キナーゼインヒビターが、アルボシジブである、請求項28に記載の医薬組成物。
- 前記ヒストンデアセチラーゼインヒビターが、パノビノスタットである、請求項28または29のいずれか一項に記載の医薬組成物。
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