Abstract

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.

Data availability

The following data sets were generated
The following previously published data sets were used
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.
    1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP
    (2007) Molecular Signatures Database v5.1
    Available at the Gene Set Enrichment Analysis site (http://software.broadinstitute.org/gsea/msigdb/). Users are required to register to view the MSigDB gene sets and/or download the GSEA software.

Article and author information

Author details

  1. Paul Andrew Clarke

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    For correspondence
    paul.clarke@icr.ac.uk
    Competing interests
    Paul Andrew Clarke, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9342-1290
  2. Maria-Jesus Ortiz-Ruiz

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Maria-Jesus Ortiz-Ruiz, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  3. Robert TePoele

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Robert TePoele, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  4. Olajumoke Adeniji-Popoola

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Olajumoke Adeniji-Popoola, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  5. Gary Box

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Gary Box, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  6. Will Court

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Will Court, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  7. Stefanie Czasch

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Stefanie Czasch, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  8. Samer El Bawab

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Samer El Bawab, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  9. Christina Esdar

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Christina Esdar, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  10. Ken Ewan

    School of Bioscience, Cardiff University, Cardiff, United Kingdom
    Competing interests
    No competing interests declared.
  11. Sharon Gowan

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Sharon Gowan, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  12. Alexis De Haven Brandon

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Alexis De Haven Brandon, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  13. Phllip Hewitt

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Phllip Hewitt, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  14. Stephen M Hobbs

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Stephen M Hobbs, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  15. Wolfgang Kaufmann

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Wolfgang Kaufmann, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  16. Aurélie Mallinger

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Aurélie Mallinger, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  17. Florence Raynaud

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Florence Raynaud, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  18. Toby Roe

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Toby Roe, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  19. Felix Rohdich

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Felix Rohdich, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  20. Kai Schiemann

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Kai Schiemann, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  21. Stephanie Simon

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Stephanie Simon, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  22. Richard Schneider

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Richard Schneider, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  23. Melanie Valenti

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Melanie Valenti, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  24. Stefan Weigt

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Stefan Weigt, KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  25. Julian Blagg

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Julian Blagg, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  26. Andree Blaukat

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Andree Blaukat, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  27. Trevor C Dale

    School of Bioscience, Cardiff University, Cardiff, United Kingdom
    For correspondence
    daletc@cardiff.ac.uk
    Competing interests
    No competing interests declared.
  28. Suzanne A Eccles

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    Suzanne A Eccles, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  29. Stefan Hecht

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Stefan Hecht, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  30. Klaus Urbahns

    Merck KGaA, Darmstadt, Germany
    Competing interests
    Klaus Urbahns, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.
  31. Paul Workman

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    For correspondence
    paul.workman@icr.ac.uk
    Competing interests
    Paul Workman, Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors.
  32. Dirk Wienke

    Merck KGaA, Darmstadt, Germany
    For correspondence
    dirk.wienke@merckgroup.com
    Competing interests
    Dirk Wienke, Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors.

Funding

Cancer Research UK (C309/A11566, C368/A6743, A368/A7990)

  • Paul Workman

Breast Cancer Now (2008MayPR16)

  • Trevor C Dale

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

Ethics

Animal experimentation: In the UK, all animal work was conducted in accordance with National Institute for Cancer Research guidelines, with the research programme and procedures approved by the local Animal Welfare and Ethical Review Boards and subject to UK Government Home Office regulations (Licence PPL 70/7635 & PPL 30/3279). In Germany the animal work was carried out in accordance with the German Law on the Protection of Animals (Article 8a) and the pertaining files at the at the local animal welfare authorities in Darmstadt and Freiburg bear the references DA/375, DA4/1003, DA4/1004 and G13/13 respectively. The studies were designed in accordance with presently valid international study guidelines (e.g. ICH guideline M3 R2) and performed in compliance with animal health and welfare guidelines.The Institute of Cancer Research does not use non-rodent species in research and, where this is deemed essential, requires ethical approval for use by organizations with whom we collaborate. Pharmacokinetic and tolerability analysis of compounds in dogs, necessary for prediction of human pharmacokinetics, was approved by the ICR Animal Welfare and Ethical Review Board. Studies were sponsored and conducted in full compliance with national regulations at an Association for Assessment and Accreditation of Laboratory Animal Care accredited site of Merck Biopharma.

Copyright

© 2016, Clarke 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. Paul Andrew Clarke
  2. Maria-Jesus Ortiz-Ruiz
  3. Robert TePoele
  4. Olajumoke Adeniji-Popoola
  5. Gary Box
  6. Will Court
  7. Stefanie Czasch
  8. Samer El Bawab
  9. Christina Esdar
  10. Ken Ewan
  11. Sharon Gowan
  12. Alexis De Haven Brandon
  13. Phllip Hewitt
  14. Stephen M Hobbs
  15. Wolfgang Kaufmann
  16. Aurélie Mallinger
  17. Florence Raynaud
  18. Toby Roe
  19. Felix Rohdich
  20. Kai Schiemann
  21. Stephanie Simon
  22. Richard Schneider
  23. Melanie Valenti
  24. Stefan Weigt
  25. Julian Blagg
  26. Andree Blaukat
  27. Trevor C Dale
  28. Suzanne A Eccles
  29. Stefan Hecht
  30. Klaus Urbahns
  31. Paul Workman
  32. Dirk Wienke
(2016)
Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases
eLife 5:e20722.
https://doi.org/10.7554/eLife.20722

Share this article

https://doi.org/10.7554/eLife.20722

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