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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2019, 62, 20, 9175-9187
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Identification of 2,6-Disubstituted 3H-Imidazo[4,5-b]pyridines as Therapeutic Agents for Dysferlinopathies through Phenotypic Screening on Patient-Derived Induced Pluripotent Stem Cells

  • Hiroyuki Takada*
    Hiroyuki Takada
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
    *E-mail: [email protected]. Phone: (+81)466-32-2076. Fax: (+81)466-29-4449.
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    Orcidhttp://orcid.org/0000-0001-6650-7902
    • , 
  • Akira Kaieda
    Akira Kaieda
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    Orcidhttp://orcid.org/0000-0003-1782-2345
    • , 
  • Michiko Tawada
    Michiko Tawada
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Tomoko Nagino
    Tomoko Nagino
    T-CiRA Discovery, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Katsunori Sasa
    Katsunori Sasa
    T-CiRA Discovery, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Tatsuo Oikawa
    Tatsuo Oikawa
    T-CiRA Discovery, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Akiko Oki
    Akiko Oki
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Tomoya Sameshima
    Tomoya Sameshima
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    Orcidhttp://orcid.org/0000-0002-3580-3095
    • , 
  • Kazumasa Miyamoto
    Kazumasa Miyamoto
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Makoto Miyamoto
    Makoto Miyamoto
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Yuko Kokubu
    Yuko Kokubu
    Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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    • , 
  • Ryuichi Tozawa
    Ryuichi Tozawa
    T-CiRA Discovery, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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    • , 
  • Hidetoshi Sakurai
    Hidetoshi Sakurai
    Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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    • , and 
  • Bunnai Saito
    Bunnai Saito
    Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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Cite this: J. Med. Chem. 2019, 62, 20, 9175–9187
Publication Date (Web):September 24, 2019
https://doi.org/10.1021/acs.jmedchem.9b01100
Copyright © 2019 American Chemical Society
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Abstract

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Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to the lack of therapeutic agents. Herein, we report the design, synthesis, and structure–activity relationships of a 2,6-disubstituted 3H-imidazo[4,5-b]pyridine series, which was identified from the phenotypic screening of chemicals that increase the level of dysferlin in myocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). Optimization studies with cell-based phenotypic assay led to the identification of a highly potent compound, 19, with dysferlin elevation effects at double-digit nanomolar concentrations. In addition, the molecular target of our chemical series was identified as tubulin, through a tubulin polymerization assay and a competitive binding assay using a photoaffinity labeling probe.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b01100.

  • The structure, EC150 value, and MEC value of compounds tested in the tubulin depolymerization assay, preparation of compounds S1–S6, and results of TR-FRET based competitive binding assays against 337 kinases (PDF)

  • Molecular formula strings (CSV)

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