Development of small molecule chimeras that recruit a new E3 ligase to target proteins

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06567
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Ohoka Nobumichi 国立医薬品食品衛生研究所, 遺伝子医薬部, 室長 (80568519)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: PROTAC / ユビキチン / プロテアソーム / 標的タンパク質分解 / キメラ化合物

Outline of Final Research Achievements

Targeted protein degradation using chimeric small molecules (PROTACs and SNIPERs) is an emerging modality in drug discovery. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand, we developed a novel class of chimeric molecules that recruit the AhR E3 ligase complex. β-NF-ATRA, a chimeric degrader directed against CRABPs, induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. Finally, we developed a chimeric compound β-NF-JQ1 that is directed against BRD proteins. β-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules that recruit an AhR E3 ligase to target proteins.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

プロテインノックダウン法は、リガンドを置換することで様々なタンパク質を標的とすることが可能な汎用性の高い技術である。また、E3リガーゼに関しても様々なE3を利用できると考えられるが、そのために必要なリガンド化合物（E3リガンド）はほとんど見つかっていない。本研究では、標的タンパク質のユビキチン化に利用できるE3リガーゼ（およびE3リガンド）のレパートリーを増やすことに成功した。本成果により、プロテインノックダウン法の汎用性がさらに高まる（標的タンパク質の適応範囲が広がる）ことが期待できる。