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2023 年度 実績報告書

STAT3を分解するPROTAC/SNIPERの分子設計、合成と活性評価

研究課題

研究課題/領域番号 22KF0090
配分区分基金
研究機関東京大学

研究代表者

内藤 幹彦  東京大学, 大学院薬学系研究科(薬学部), 特任教授 (00198011)

研究分担者 SHIH PO-CHANG  東京大学, 大学院薬学系研究科(薬学部), 外国人特別研究員
研究期間 (年度) 2023-03-08 – 2024-03-31
キーワードprotein degradation / PROTAC / STAT3 / Nucleic acids
研究実績の概要

Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in the drug development community. Recently, oligonucleotide-warheaded PROTACs have emerged as a promising new tool to degrade DNA-binding proteins such as transcription factors. In this study, we applied an oligonucleotide-warheaded PROTAC technology to induce the degradation of signal transducer and activator of transcription 3 (STAT3), which is a hard-to-target protein. A double-stranded decoy oligonucleotide specific to STAT3 was conjugated to pomalidomide, VH032, and LCL161 to generate PROTAC molecules that recruited different E3 ubiquitin ligases CRBN, VHL and IAP, respectively. One of the resulting PROTAC molecules, POM-STAT3, which recruits CRBN, potently induces STAT3 degradation. STAT3 degradation by POM-STAT3 was abolished by scrambling the oligonucleotide sequences of POM-STAT3 and by adding a double-stranded decoy oligonucleotide against STAT3 in a competitive manner, suggesting the significance of oligonucleotide sequences in STAT3 degradation. Moreover, POM-STAT3-induced STAT3 degradation was suppressed by the CRBN binder thalidomide, proteasome inhibitor bortezomib, E1 inhibitor MLN7243, indicating that STAT3 degradation is mediated by the ubiquitin-proteasome system, which involves CRBN as the responsible E3 ubiquitin ligase. Consistent with STAT3 degradation, NCI-H2087 cell viability was severely reduced following POM-STAT3 treatment. Thus, POM-STAT3 is a STAT3 degrader that potentially has cytocidal activity against cancer cells that are highly dependent on STAT3 signaling.

  • 研究成果

    (2件)

すべて 2023 その他

すべて 雑誌論文 (1件) (うち査読あり 1件) 備考 (1件)

  • [雑誌論文] Development of decoy oligonucleotide-warheaded chimeric molecules targeting STAT32023

    • 著者名/発表者名
      Shih Po-Chang、Naganuma Miyako、Tsuji Genichiro、Demizu Yosuke、Naito Mikihiko
    • 雑誌名

      Bioorganic & Medicinal Chemistry

      巻: 95 ページ: 117507~117507

    • DOI

      10.1016/j.bmc.2023.117507

    • 査読あり
  • [備考] 東京大学大学院薬学系研究科タンパク質分解創薬社会連携講座HP

    • URL

      https://tpd.f.u-tokyo.ac.jp

URL: 

公開日: 2024-12-25  

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