Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action

  1. Jonathan Baruch Steinman
  2. Cristina C Santarossa
  3. Rand M Miller
  4. Lola S Yu
  5. Anna S Serpinskaya
  6. Hideki Furukawa
  7. Sachie Morimoto
  8. Yuta Tanaka
  9. Mitsuyoshi Nishitani
  10. Moriteru Asano
  11. Ruta Zalyte
  12. Alison E Ondrus
  13. Alex G Johnson
  14. Fan Ye
  15. Maxence V Nachury
  16. Yoshiyuki Fukase
  17. Kazuyoshi Aso
  18. Michael A Foley
  19. Vladimir I Gelfand
  20. James K Chen
  21. Andrew P Carter
  22. Tarun M Kapoor  Is a corresponding author
  1. Rockefeller University, United States
  2. Feinberg School of Medicine, Northwestern University, United States
  3. Tri-Institutitional Therapeutics Discovery Institute, United States
  4. Takeda Pharmaceuticals Ltd., Japan
  5. MRC Laboratory of Molecular Biology, United Kingdom
  6. California Institute of Technology, United States
  7. Stanford University, United States
  8. Stanford University School of Medicine, United States
  9. Northwestern University, United States

Abstract

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that power transport of cellular cargos towards microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally-constrained isosteres. We identified dynapyrazoles, inhibitors more potent than ciliobrevins in vitro, and find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles block only microtubule-stimulated activity. Single-digit micromolar concentrations of dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Together, our studies suggest that chemical structure-based analyses can lead to inhibitors with distinct modes of inhibition and improved properties.

Article and author information

Author details

  1. Jonathan Baruch Steinman

    Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Cristina C Santarossa

    Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Rand M Miller

    Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lola S Yu

    Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna S Serpinskaya

    Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hideki Furukawa

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sachie Morimoto

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yuta Tanaka

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mitsuyoshi Nishitani

    Pharmaceutical Research Division, Takeda Pharmaceuticals Ltd., Kanagawa, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Moriteru Asano

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ruta Zalyte

    Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Alison E Ondrus

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Alex G Johnson

    Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Fan Ye

    Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Maxence V Nachury

    Deptartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Yoshiyuki Fukase

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Kazuyoshi Aso

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Michael A Foley

    Tri-Institutitional Therapeutics Discovery Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Vladimir I Gelfand

    Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. James K Chen

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Andrew P Carter

    Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  22. Tarun M Kapoor

    Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States
    For correspondence
    kapoor@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0628-211X

Funding

National Institutes of Health (R01 GM098579)

  • Tarun M Kapoor

Robertson Therapeutic Development Fund

  • Tarun M Kapoor

Damon Runyon Cancer Research Foundation (DRG-2222-15)

  • Rand M Miller

Medical Research Council (MC_UP_A025_1011)

  • Andrew P Carter

National Institutes of Health (T32GM007739)

  • Jonathan Baruch Steinman

National Institutes of Health (R01 GM52111)

  • Vladimir I Gelfand

National Institutes of Health (R01 GM113100)

  • James K Chen

Wellcome (WT100387)

  • Andrew P Carter

National Institutes of Health (R01 GM089933)

  • Maxence V Nachury

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wilfred A van der Donk, University of Illinois at Urbana-Champaign, United States

Publication history

  1. Received: January 20, 2017
  2. Accepted: May 17, 2017
  3. Accepted Manuscript published: May 19, 2017 (version 1)
  4. Version of Record published: June 20, 2017 (version 2)

Copyright

© 2017, Steinman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jonathan Baruch Steinman
  2. Cristina C Santarossa
  3. Rand M Miller
  4. Lola S Yu
  5. Anna S Serpinskaya
  6. Hideki Furukawa
  7. Sachie Morimoto
  8. Yuta Tanaka
  9. Mitsuyoshi Nishitani
  10. Moriteru Asano
  11. Ruta Zalyte
  12. Alison E Ondrus
  13. Alex G Johnson
  14. Fan Ye
  15. Maxence V Nachury
  16. Yoshiyuki Fukase
  17. Kazuyoshi Aso
  18. Michael A Foley
  19. Vladimir I Gelfand
  20. James K Chen
  21. Andrew P Carter
  22. Tarun M Kapoor
(2017)
Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action
eLife 6:e25174.
https://doi.org/10.7554/eLife.25174

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