PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase

  • Nat Chem Biol. 2020 Nov;16(11):1179-1188. doi: 10.1038/s41589-020-00652-y.
Bikash Adhikari   #  1 ,  Jelena Bozilovic   #  2  3 ,  Mathias Diebold  4 ,  Jessica Denise Schwarz  1 ,  Julia Hofstetter  1 ,  Martin Schröder  2 ,  Marek Wanior  2 ,  Ashwin Narain  1 ,  Markus Vogt  1 ,  Nevenka Dudvarski Stankovic  1 ,  Apoorva Baluapuri  1 ,  Lars Schönemann  5 ,  Lorenz Eing  1 ,  Pranjali Bhandare  1 ,  Bernhard Kuster  3  6  7 ,  Andreas Schlosser  5 ,  Stephanie Heinzlmeir  6 ,  Christoph Sotriffer  4 ,  Stefan Knapp  8  9 ,  Elmar Wolf  10
Affiliations
  • 1. Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany.
  • 2. Institut für Pharmazeutische Chemie und Structural Genomics Consortium, Goethe-Universität Frankfurt, Frankfurt am Main, Germany.
  • 3. German Cancer Consortium (DKTK)/German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 4. Institut für Pharmazie und Lebensmittelchemie, University of Würzburg, Würzburg, Germany.
  • 5. Rudolf Virchow Center - Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
  • 6. Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.
  • 7. Bavarian Biomolecular Mass Spectrometry Center (BayBioMS), Technical University of Munich, Freising, Germany.
  • 8. Institut für Pharmazeutische Chemie und Structural Genomics Consortium, Goethe-Universität Frankfurt, Frankfurt am Main, Germany. [email protected].
  • 9. German Cancer Consortium (DKTK)/German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
  • 10. Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany. [email protected].
  • # Contributed equally.
PMID: 32989298 DOI: 10.1038/s41589-020-00652-y
Abstract

The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority Cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (for example, thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition, we found that the degrader complex was stabilized by cooperative binding between AURORA-A and Cereblon. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant Apoptosis in Cancer cell lines and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in Cancer.

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