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A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63-43F2

  • The Journal of Antibiotics volume 71, pages 135138 (2018)
  • doi:10.1038/ja.2017.100
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Abstract

Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK. We performed a screening to discover new MEK inhibitors, and found a guanine derivative produced by Streptomyces sp. MK63-43F2. This guanine derivative was identified to be 2-amino-4-methoxy-5-cyanopyrrolo[2,3-d]pyrimidine (1) through spectroscopic analysis. Compound 1 inhibited MEK1 kinase activity in an ATP-dependent manner and suppressed the phosphorylation of ERK in cancer cells and cell proliferation. Therefore, 1 might be a potent lead compound for new MEK inhibitors.

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GenBank/EMBL/DDBJ

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Acknowledgements

We thank Drs N Noda and Y Fujioka for helpful advice, and Ms T Yoshida, Ms S Takahashi and Ms S Kakuda for technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research (16H06574, 15H04703 and 17K08650) from the Japan Society for the Promotion of Science (JSPS; MT and Yuji Kubota) and by grants from the Princess Takamatsu Cancer Research Fund, the Mitsubishi foundation and the Tokyo Biochemical Research Foundation (MT).

Author information

Author notes

    • Masatomi Iijima
    •  & Yuji Kubota

    These authors contributed equally to this work.

Affiliations

  1. Institute of Microbial Chemistry (BIKAKEN), Shizuoka, Japan

    • Masatomi Iijima
    • , Manabu Kawada
    •  & Isao Momose
  2. Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    • Yuji Kubota
    •  & Mutsuhiro Takekawa
  3. Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan

    • Ryuichi Sawa
    • , Yumiko Kubota
    • , Masaki Hatano
    • , Masayuki Igarashi
    •  & Masakatsu Shibasaki

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to Isao Momose or Mutsuhiro Takekawa.

Supplementary information

Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)