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

• Published in: Nature chemical biology Vol. 16; no. 11; pp. 1179 - 1188
• Main Authors: Adhikari, Bikash, Bozilovic, Jelena, Diebold, Mathias, Schwarz, Jessica Denise, Hofstetter, Julia, Schröder, Martin, Wanior, Marek, Narain, Ashwin, Vogt, Markus, Dudvarski Stankovic, Nevenka, Baluapuri, Apoorva, Schönemann, Lars, Eing, Lorenz, Bhandare, Pranjali, Kuster, Bernhard, Schlosser, Andreas, Heinzlmeir, Stephanie, Sotriffer, Christoph, Knapp, Stefan, Wolf, Elmar
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 631/154/309; 631/45/275; 631/67; 631/80/641; 631/92/613; Adaptor Proteins, Signal Transducing - metabolism; Antineoplastic Agents - chemistry; Apoptosis; Apoptosis - drug effects; Aurora Kinase A - antagonists & inhibitors; Aurora Kinase A - genetics; Benzazepines - chemistry; Binding; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Biotechnology; Cancer; Catalytic activity; Catalytic Domain; Cell Biology; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Chemical degradation; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Depletion; DNA biosynthesis; DNA Replication - drug effects; Drug Design; Enzyme inhibitors; Female; Humans; Kinases; Male; Molecular Targeted Therapy; Polyethylene Glycols - chemistry; Protein Binding; Protein Conformation; Protein Kinase Inhibitors - chemistry; Proteolysis - drug effects; Thalidomide; Thalidomide - chemistry; Tumor cell lines; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/s41589-020-00652-y

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. A bifunctional AURORA-A degrader induces the fast and specific degradation of this kinase in cancer cell lines, which enables targeting of non-catalytic, oncogenic functions of AURORA-A resulting in S-phase arrest and rampant apoptosis.