2. Academic Validation
  3. PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase

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

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. knapp@pharmchem.uni-frankfurt.de.
  • 9 German Cancer Consortium (DKTK)/German Cancer Research Center (DKFZ), Heidelberg, Germany. knapp@pharmchem.uni-frankfurt.de.
  • 10 Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany. elmar.wolf@biozentrum.uni-wuerzburg.de.
  • # 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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