WO2006126505A1 - Stat function inhibitor and application thereof - Google Patents

Stat function inhibitor and application thereof Download PDF

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Publication number
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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stat
nuclear
ezi
migration
inhibitor according
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PCT/JP2006/310187
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French (fr)
Japanese (ja)
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Atsushi Miyajima
Kyung-Woon Kim
Tohru Itoh
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The University Of Tokyo
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Publication of WO2006126505A1 publication Critical patent/WO2006126505A1/en

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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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

Abstract

When the expression of an EZI gene is inhibited using synthetic oligo-siRNA which targets the EZI gene or siRNA which has been expressed using a vector, the nuclear translocation of STAT3 and the activation of the expression of a STAT3-dependent gene are suppressed. A nucleic acid having a modification in an APRE sequence to which EZI protein and STAT3 protein can bind in the α2-macroglobulin promoter region inhibits the nuclear translocation/subcellular localization of STAT protein by EZI protein and also inhibits the activation of the expression of an STAT3-dependent gene. It is also found that a synthetic peptide having a cell membrane penetration signal bound to an STAT3-binding peptide on EZI protein inhibits the nuclear translocation/subcellular localization of STAT by EZI protein and the activation of the expression of an STAT-dependent gene and also inhibits the growth of cancer cells.

Description

明 細 書  Specification
STAT機能阻害剤およびその応用  STAT function inhibitors and their applications
技術分野  Technical field
[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。  [0001] 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.
背景技術  Background art
[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。  [0002] 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.
[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  [0003] 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). (Non-patent literature 2-6). 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. By cell
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)。  It is involved in the promotion of growth and suppression of apoptosis (Non-Patent Documents 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 [0004] In fact, the constant activity of STAT3 is prostate cancer, breast cancer, head and neck cancer, leukemia

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。 Claims [I] A STAT nuclear migration / nuclear localization inhibitor comprising any of the following (1) or (2):
(1) EZI遺伝子の転写または翻訳産物に結合し得る物質  (1) Substances that can bind to transcription or translation products of EZI gene
(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 partial peptide consisting of the amino acid sequence described in SEQ ID NO: 22 or 23, a part thereof, or a modification thereof
[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 [2] The S according to claim 1, wherein the substance capable of binding to the transcription or translation product of the EZI gene is a nucleic acid.
TAT核移動/核局在阻害剤。 TAT nuclear migration / localization inhibitor.
[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[3] Ribonucleotides that can bind to transcripts of EZI gene or D encoding this
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。 3. The STAT nuclear migration / nuclear localization inhibitor according to claim 2, which is a vector carrying NA.
[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。 [4] The STAT nuclear migration / nuclear localization inhibitor according to claim 3, wherein the ribonucleotide is a double strand.
[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。 [5] The STAT nuclear migration / nuclear localization inhibitor according to claim 3 or 4, wherein the ribonucleotide has a sequence corresponding to a sequence of 16 bases or more in the EZI gene.
[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。 [6] The STAT nuclear migration / nuclear localization inhibitor according to claim 5, which has a sequence corresponding to any one of SEQ ID NOs: 1-4 or 11-13.
[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。 [7] The STAT nuclear migration / nuclear localization inhibitor according to claim 2, wherein the nucleic acid is an oligonucleotide in a gene regulatory region to which an EZI gene translation product can bind or a variant thereof.
[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。 [8] The STAT nuclear migration / nuclear localization inhibitor according to claim 7, which is A / or a part of APRE in the α2-macroglobulin promoter region, or a part thereof, or an oligonucleotide obtained by modifying them.
[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。  [9] The STAT nuclear migration / nuclear localization inhibitor according to claim 8, which has any one of SEQ ID NOs: 15 to 20.
[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。  [10] The STAT nuclear migration / nuclear localization inhibitor according to claim 8, which has any one of SEQ ID NOs: 16, 17, and 20.
[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。  [II] The STAT nuclear migration / nuclear localization inhibitor according to claim 1, which is an EZI partial peptide force TAT-binding region or a part thereof.
[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。 [12] As a part of the STAT binding region, any one or more of regions 99 to 101, 106 to 108, or 163 to 164 in the amino acid sequence shown in SEQ ID NO: 34 or 36 The STAT nuclear migration / nuclear localization inhibitor according to claim 11, comprising:
[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。 [13] The STAT nuclear migration / nuclear localization inhibitor according to any one of claims 1, 11, and 12, wherein the variant is an EZI partial peptide or a peptide obtained by adding a nuclear translocation signal to a part thereof.
[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。  [14] The STAT nuclear migration / nuclear localization inhibitor according to claim 13, which also has the alignment ability according to any one of SEQ ID NOs: 25 to 27 and 29 to 31.
[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。  [15] The STAT nuclear migration / nuclear localization inhibitor according to any one of claims 1 to 14, which has a STAT force TAT3.
[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。  [16] A STAT-dependent gene expression regulation inhibitor comprising the STAT nuclear migration / nuclear localization inhibitor according to any one of claims 1 to 15.
[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。 [17] A cancer cell growth inhibitor comprising the STAT nuclear migration / nuclear localization inhibitor according to any one of claims 1 to 15.
[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。  [18] A pharmaceutical composition for treating / preventing a disease caused by STAT-dependent gene expression regulation, comprising the STAT nuclear migration / nuclear localization inhibitor according to any one of claims 1 to 15.
[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。  [19] (0 STAT nuclear migration / nuclear localization inhibitor, comprising the step of measuring the binding activity between the test substance and EZI, or the measurement of the binding activity between the GO test substance and EZI and STAT, STAT-dependent gene expression inhibitor, screening method for pharmaceutical composition for treatment / prevention of diseases caused by STAT-dependent gene expression.
[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。  [20] The screening method according to claim 19, further comprising one or more of the following steps (1) to (4):
(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  (1) Measuring the binding ability of EZI and STAT in the presence of the test substance
(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  (2) A step of measuring the localization of EZI after adding a STAT stimulating factor by allowing a test substance to act on cells expressing EZI
(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  (3) The step of measuring the localization of STAT after adding STAT stimulating factor by allowing EZI and STAT to be expressed and causing the test substance to act on the cells
(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  (4) A step of measuring the STAT-dependent gene expression after adding a STAT stimulating factor by allowing a test substance to act on cells that express EZI and STAT.
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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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