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WO2006126505A1 - Stat機能阻害剤およびその応用 - Google Patents

Stat機能阻害剤およびその応用 Download PDF

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WO2006126505A1
WO2006126505A1 PCT/JP2006/310187 JP2006310187W WO2006126505A1 WO 2006126505 A1 WO2006126505 A1 WO 2006126505A1 JP 2006310187 W JP2006310187 W JP 2006310187W WO 2006126505 A1 WO2006126505 A1 WO 2006126505A1
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nuclear
ezi
migration
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Atsushi Miyajima
Kyung-Woon Kim
Tohru Itoh
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University of Tokyo NUC
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Definitions

  • the present invention relates to a substance capable of suppressing the expression or function of an EZI protein (endothelial cell-derived zinc-finger protein) capable of binding to a STAT (signal transducer and activator of transcription) protein, or a STAT protein and an EZI protein.
  • the present invention relates to an inhibitor of STAT nuclear migration / localization, a STAT-dependent gene expression inhibitor, a cancer cell growth inhibitor, and applications thereof using substances capable of inhibiting the interaction with STAT.
  • the family of STAT transcription factors plays a major role downstream of receptors for cytoforce-in receptors and interferon receptors and several growth factors.
  • the STAT protein is a so-called “latent” transcription factor and is present in the cytoplasm in a steady state (ie, unstimulated). When stimulated by a ligand, the STAT protein binds to the cytoforce in / interferon receptor and undergoes tyrosine phosphorylation by the action of an endogenous kinase domain encoded within the JAK family tyrosine kinase or growth factor receptor. .
  • a STAT protein that has undergone tyrosine phosphorylation forms a homodimer or a heterodimer by the interaction of the phosphotyrosine residue of one STAT molecule with the SH2 domain of the other STAT molecule.
  • the dimerized STAT then moves to the nucleus where it binds to specific DNA sequences and regulates the transcription of the target gene.
  • STAT3 There are seven types of STAT molecules in mammals, of which STAT3 is considered the most prototype.
  • STAT3 is known to be activated by many site force-ins such as the interleukin (IL) -6 family including Oncostatin M (OSM) and growth factors such as epidermal growth factor (EGF).
  • IL interleukin
  • OSM Oncostatin M
  • EGF epidermal growth factor
  • STAT3 exerts many different biological functions depending on the state of the cell in which it is expressed, but its main role is to induce a variety of important target genes, including c-myc and bd-x.
  • Non-Patent Documents 8, 9, 10 It is involved in the promotion of growth and suppression of apoptosis.
  • the constant activity of STAT3 is prostate cancer, breast cancer, head and neck cancer, leukemia

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Abstract

　EZI遺伝子を標的とする合成オリゴsiRNAまたはベクターより発現させたsiRNAを用いて、EZI遺伝子の発現を抑制した結果、STAT３の核移行およびSTAT3依存性遺伝子発現活性化が抑制された。α2－マクログロブリンプロモーター領域中のEZIタンパク質およびSTAT３タンパク質が結合するAPRE配列を改変した核酸が、EZIタンパク質によるSTATタンパク質の核移動/核局在化を阻害し、さらにはSTAT依存的な遺伝子発現活性化をも抑制した。また、EZIタンパク質上のSTAT３結合ペプチドに細胞膜浸透シグナルを結合させた合成ペプチドはEZIタンパク質によるSTATの核移動/核局在化、STAT依存的な遺伝子発現活性化を抑制し、さらには、がん細胞増殖を抑制することを見出した。

Description

明 細 書
STAT機能阻害剤およびその応用
技術分野
[0001] 本発明は、 STAT(signal transducer and activator of transcription)タンパク質と結合 し得る EZIタンパク質（endothelial cell-derived zinc-finger protein)の発現もしくはそ の機能を抑制し得る物質または STATタンパク質と EZIタンパク質との相互作用を阻害 し得る物質を利用した STAT核移動/局在化の阻害剤、 STAT依存性遺伝子発現調 節阻害剤、がん細胞増殖抑制剤およびこれらの応用に関する。
背景技術
[0002] STAT転写因子ファミリ一は、サイト力イン受容体およびインターフェロン受容体なら びにいくつかの成長因子に対する受容体の下流で主な役割を果たしている。 STAT タンパク質は、いわゆる「潜在的」転写因子であり、定常状態 (すなわち、刺激されて いない状態)で細胞質内に存在する。リガンドにより刺激されると、 STATタンパク質は 、サイト力イン/インターフェロン受容体に結合して 、る JAKファミリーチロシンキナーゼ または成長因子受容体内にコードされている内在性キナーゼドメインの作用によって チロシンリン酸化を受ける。チロシンリン酸化を受けた STATタンパク質は、一方の ST AT分子のホスホチロシン残基と他方の STAT分子の SH2ドメインとの相互作用によつ てホモ二量体またはへテロ二量体を形成する。次いで、二量体ィ匕した STATは核に 移動し、そこで特定の DNA配列に結合し、標的遺伝子の転写を調節する。
[0003] 哺乳動物には 7種類の STAT分子があり、そのうち STAT3は最もプロトタイプのもの であると考えられている。 STAT3は、オンコスタチン M(OSM)を含むインターロイキン (I L)-6ファミリーなどの多くのサイト力インや、上皮細胞成長因子 (EGF)などの増殖因子 によって活性ィ匕されることが知られている（非特許文献 2— 6)。 STAT3は、その発現 する細胞の状態に応じて、多くの異なる生物学的機能を発揮するが、その主な役割 は、 c-mycおよび bd-xを含む様々な重要な標的遺伝子を誘導することによって細胞 し
の増殖の促進やアポトーシスの抑制に関わる（非特許文献 8、 9、 10)。
[0004] 実際に、 STAT3の恒常的な活性ィ匕が前立腺がん、乳がん、頭頸部がん、白血病な

Claims

請求の範囲 [I] 下記（1)または（2)のいずれかを含む、 STAT核移動/核局在阻害剤。
(1) EZI遺伝子の転写または翻訳産物に結合し得る物質
(2)配列番号： 22または 23に記載されたアミノ酸配列からなる EZI部分ペプチドもしく はその一部またはそれらの改変体
[2] EZI遺伝子の転写または翻訳産物に結合し得る物質が核酸である、請求項 1記載の S
TAT核移動/核局在阻害剤。
[3] 核酸が EZI遺伝子の転写産物に結合し得るリボヌクレオチドまたはこれをコードした D
NAを担持したベクターである、請求項 2記載の STAT核移動/核局在阻害剤。
[4] リボヌクレオチドが二重鎖である、請求項 3記載の STAT核移動/核局在阻害剤。
[5] リボヌクレオチドが EZI遺伝子中の連続する 16塩基以上の配列に対応した配列を有 する、請求項 3または 4記載の STAT核移動/核局在阻害剤。
[6] 配列番号 1〜4または 11〜13のいずれかの配列に対応した配列を有する、請求項 5 記載の STAT核移動/核局在阻害剤。
[7] 核酸が、 EZI遺伝子翻訳産物が結合し得る遺伝子制御領域中のオリゴヌクレオチドま たはその改変体である、請求項 2記載の STAT核移動/核局在阻害剤。
[8] α 2—マクログロブリンプロモーター領域中の APREもしくはその一部、またはこれらを 改変したオリゴヌクレオチドの!/、ずれかである、請求項 7記載の STAT核移動/核局在 阻害剤。
[9] 配列番号 15〜20のいずれかの配列を有する、請求項 8記載の STAT核移動/核局 在阻害剤。
[10] 配列番号 16、 17または 20のいずれかの配列を有する、請求項 8記載の STAT核移 動/核局在阻害剤。
[II] EZI部分ペプチド力 TAT結合領域またはその一部である、請求項 1記載の STAT核 移動/核局在阻害剤。
[12] STAT結合領域の一部には、配列番号 34または 36に記載のアミノ酸配列における 99 番から 101番、 106番から 108番、または 163番から 164番のいずれか一つ以上の領域 を含む、請求項 11記載の STAT核移動/核局在阻害剤。
[13] 改変体が EZI部分ペプチドまたはその一部に核移行シグナルを付加したペプチドで ある、請求項 1、 11、 12のいずれかに記載の STAT核移動/核局在阻害剤。
[14] 配列番号 25〜27、 29〜31のいずれかに記載の配列力もなる、請求項 13記載の ST AT核移動/核局在阻害剤。
[15] STAT力 TAT3である、請求項 1〜14のいずれかに記載の STAT核移動/核局在阻 害剤。
[16] 請求項 1〜15のいずれか〖こ記載の STAT核移動/核局在阻害剤を含む、 STAT依存 性遺伝子発現調節阻害剤。
[17] 請求項 1〜15のいずれかに記載の STAT核移動/核局在阻害剤を含む、がん細胞増 殖抑制剤。
[18] 請求項 1〜15のいずれか〖こ記載の STAT核移動/核局在阻害剤を含む、 STAT依存 性遺伝子発現調節に起因する疾患の治療 ·予防用医薬組成物。
[19] (0 被験物質と EZIとの結合活性を測定する工程、または GO被験物質と EZIならびに STATとのそれぞれの結合活性を測定する工程を含む、 STAT核移動/核局在化阻害 剤、 STAT依存性遺伝子発現抑制剤、 STAT依存性遺伝子発現が起因する疾患の治 療 ·予防用医薬組成物のスクリーニング方法。
[20] 以下（1)〜 (4)の一つ以上の工程をさらに含む、請求項 19記載のスクリーニング方 法。
(1)被験物質存在下での EZIと STATとの結合能を測定する工程
(2) EZIが発現して ヽる細胞に被験物質を作用させ、 STAT刺激因子添加後の EZI の局在を測定する工程
(3) EZIおよび STATが発現して 、る細胞に被験物質を作用させ、 STAT刺激因子添 加後の STATの局在を測定する工程
(4) EZIおよび STATが発現して 、る細胞に被験物質を作用させ、 STAT刺激因子添 加後の STAT依存的な遺伝子発現を測定する工程
PCT/JP2006/310187 2005-05-26 2006-05-23 Stat機能阻害剤およびその応用 Ceased WO2006126505A1 (ja)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019073560A (ja) * 2007-09-10 2019-05-16 ボストン バイオメディカル， インコーポレイテッド 新規のＳｔａｔ３経路阻害剤及び癌幹細胞阻害剤
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US11299469B2 (en) 2016-11-29 2022-04-12 Sumitomo Dainippon Pharma Oncology, Inc. Naphthofuran derivatives, preparation, and methods of use thereof

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