2021 Fiscal Year Final Research Report
Chemical biology on a bioactive substance regulating the hypoxia response signal
Project/Area Number |
19H02840
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
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Research Institution | Kyoto University |
Principal Investigator |
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | ケミカルバイオロジー / 低酸素誘導因子 / 抗がん剤 / 天然物化学 / 分子プローブ |
Outline of Final Research Achievements |
HIFs are promising molecular targets for cancer chemotherapy. Among HIFs family, HIF-2 promotes pVHL-deficient renal carcinoma. Thus, development of HIF-2 inhibitors is a promising therapeutic strategy for HIF-2α-driven tumors such as ccRCC (clear cell renal cell carcinoma). In this research, we found saccharothriolides (STLs), microbial metabolites produced by a rare actinomycete Saccharothrix sp., exhibited selective cytotoxic activity in VHL-deficient RCC4 cells via decrease of a protein level of HIF-2α. Next, to obtain further scarce derivatives of STLs, our original highly sensitive labeling probe was developed. The crude extract of the actinomycete was directly treated with the labeling reagent, enabling us to the detection of a new derivative preSTL-Z, whose chemical structure was confirmed by the first chemical synthesis of saccharothriolide-class macrolides. This total synthesis enabled us the structural elucidation and bioassay of STL-Z.
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Free Research Field |
ケミカルバイオロジー、天然物化学
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Academic Significance and Societal Importance of the Research Achievements |
腫瘍血管に富んだ腎細胞がんにおいては、がん抑制遺伝子vhlに異常が認められ、VHLタンパク質の機能喪失によってHIF-2αが蓄積し、多くのがん関連標的遺伝子(血管内皮増殖因子VEGFなど)が活性化されている。したがって、見出したHIF-2の機能阻害物質は、腎細胞がんをはじめとして過剰なHIF-2シグナルに起因する各種疾病のメカニズム解析用ツール及び創薬シーズとして期待される。さらに、希少天然物を高感度に検出可能な検出プローブは、いままで存在量が極微量がゆえに見出されていない様々な天然資源における希少天然物の探索・同定に利用可能である。
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