Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer

  1. Stephanie Berger  Is a corresponding author
  2. Erik Procko
  3. Daciana Margineantu
  4. Erinna F Lee
  5. Betty W Shen
  6. Alex Zelter
  7. Daniel-Adriano Silva
  8. Kusum Chawla
  9. Marco J Herold
  10. Jean-Marc Garnier
  11. Richard Johnson
  12. Michael J MacCoss
  13. Guillaume Lessene
  14. Trisha N Davis
  15. Patrick S Stayton
  16. Barry L Stoddard
  17. W Douglas Fairlie
  18. David M Hockenbery
  19. David Baker  Is a corresponding author
  1. University of Washington, United States
  2. Fred Hutchinson Cancer Research Center, United States
  3. LaTrobe Institute for Molecular Science, Australia
  4. The Walter and Eliza Hall Institute of Medical Research, Australia

Abstract

Many cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Stephanie Berger

    Department of Bioengineering, University of Washington, Seattle, United States
    For correspondence
    berger389@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3738-5907
  2. Erik Procko

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Daciana Margineantu

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Erinna F Lee

    Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Betty W Shen

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alex Zelter

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel-Adriano Silva

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kusum Chawla

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Marco J Herold

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Jean-Marc Garnier

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Richard Johnson

    Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Michael J MacCoss

    Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Guillaume Lessene

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1193-8147
  14. Trisha N Davis

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4797-3152
  15. Patrick S Stayton

    Department of Bioengineering, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Barry L Stoddard

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. W Douglas Fairlie

    Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  18. David M Hockenbery

    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. David Baker

    Department of Biochemistry, University of Washington, Seattle, United States
    For correspondence
    dabaker@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7896-6217

Funding

National Institutes of Health (P41GM103533)

  • Stephanie Berger
  • Erik Procko
  • David Baker

Australian Research Council (FT150100212)

  • Erinna F Lee

National Institutes of Health (R01 GM115545)

  • Betty W Shen
  • Barry L Stoddard

National Institutes of Health (R01 CA158921-04)

  • Daciana Margineantu
  • David M Hockenbery

Defense Threat Reduction Agency (HDTRA1-10-0040)

  • Stephanie Berger
  • Erik Procko
  • David Baker

Howard Hughes Medical Institute (HHMI-027779)

  • Stephanie Berger
  • Erik Procko
  • David Baker

National Science Foundation (Graduate Research Fellowship Program)

  • Stephanie Berger

Worldwide Cancer Research (15-0025)

  • Erinna F Lee
  • W Douglas Fairlie

Cancer Council Victoria (1057949)

  • Erinna F Lee
  • W Douglas Fairlie

Pew Charitable Trusts

  • Daniel-Adriano Silva

Consejo Nacional de Ciencia y Tecnología

  • Daniel-Adriano Silva

National Health and Medical Research Council (1024620)

  • Erinna F Lee

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

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Version history

  1. Received: August 4, 2016
  2. Accepted: November 1, 2016
  3. Accepted Manuscript published: November 2, 2016 (version 1)
  4. Version of Record published: November 29, 2016 (version 2)
  5. Version of Record updated: December 20, 2016 (version 3)

Copyright

© 2016, Berger 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. Stephanie Berger
  2. Erik Procko
  3. Daciana Margineantu
  4. Erinna F Lee
  5. Betty W Shen
  6. Alex Zelter
  7. Daniel-Adriano Silva
  8. Kusum Chawla
  9. Marco J Herold
  10. Jean-Marc Garnier
  11. Richard Johnson
  12. Michael J MacCoss
  13. Guillaume Lessene
  14. Trisha N Davis
  15. Patrick S Stayton
  16. Barry L Stoddard
  17. W Douglas Fairlie
  18. David M Hockenbery
  19. David Baker
(2016)
Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
eLife 5:e20352.
https://doi.org/10.7554/eLife.20352

Share this article

https://doi.org/10.7554/eLife.20352

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