Drugging MYCN through an allosteric transition in Aurora kinase A

  • Cancer Cell. 2014 Sep 8;26(3):414-427. doi: 10.1016/j.ccr.2014.07.015.
William Clay Gustafson  1 ,  Justin Gabriel Meyerowitz  2 ,  Erin A Nekritz  1 ,  Justin Chen  3 ,  Cyril Benes  4 ,  Elise Charron  5 ,  Erin F Simonds  6 ,  Robert Seeger  7 ,  Katherine K Matthay  1 ,  Nicholas T Hertz  8 ,  Martin Eilers  9 ,  Kevan M Shokat  10 ,  William A Weiss  11
Affiliations
  • 1. Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2. Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 3. Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 4. Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02114, USA.
  • 5. Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 6. Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 7. Division of Hematology/Oncology, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #57, Los Angeles, CA 90027, USA.
  • 8. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 9. Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Würzburg, Germany.
  • 10. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 11. Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID: 25175806 DOI: 10.1016/j.ccr.2014.07.015
Abstract

MYC proteins are major drivers of Cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity.

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