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STAT3を分解するPROTAC/SNIPERの分子設計、合成と活性評価

Research Project

Project/Area Number 22KF0090
Project/Area Number (Other) 22F22107 (2022)
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeMulti-year Fund (2023)
Single-year Grants (2022)
Section外国
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionThe University of Tokyo

Principal Investigator

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)

Co-Investigator(Kenkyū-buntansha) 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
Project Period (FY) 2023-03-08 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2023: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2022: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsprotein degradation / PROTAC / STAT3 / Nucleic acids / SNIPER
Outline of Research at the Start

STAT3は多くのがん細胞で活性の亢進が見られる転写因子であり、古くからがん治療の標的タンパク質として注目されているが、これまで有効な阻害剤は開発されていない。本研究では、STAT3を分解する新規SNIPER/PROTAC化合物を開発する事を目的とする。STAT3分解を誘導するSNIPER/PROTACは、新規抗がん剤のリード化合物となることが期待される。

Outline of Annual Research Achievements

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.

Report

(2 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • Research Products

    (4 results)

All 2023 2022 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Journal Article] Development of decoy oligonucleotide-warheaded chimeric molecules targeting STAT32023

    • Author(s)
      Shih Po-Chang、Naganuma Miyako、Tsuji Genichiro、Demizu Yosuke、Naito Mikihiko
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 95 Pages: 117507-117507

    • DOI

      10.1016/j.bmc.2023.117507

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Current Status of Oligonucleotide-Based Protein Degraders2023

    • Author(s)
      Po-Chang Shih, Miyako Naganuma, Yosuke Demizu, Mikihiko Naito
    • Journal Title

      Pharmaceutics

      Volume: 15 Issue: 3 Pages: 765-765

    • DOI

      10.3390/pharmaceutics15030765

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Towards development of protein degraders for targeting signal transducer and activator of transcription 3 (STAT3)2022

    • Author(s)
      Shih Po-C, Naganuma M, Tsuji G, Demizu Y, Naito M.
    • Organizer
      Ubiquitin New Frontier from Neo-biology to Targeted Protein Degradation
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 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

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report

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Published: 2022-04-28   Modified: 2024-12-25  

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