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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Apoptosis, Aurora Kinase A, Benzazepines, Catalytic Domain, Cell Cycle, Cell Line, Tumor, DNA Replication, Drug Design, Female, Humans, Male, Molecular Targeted Therapy, Polyethylene Glycols, Protein Binding, Protein Conformation, Protein Kinase Inhibitors, Proteolysis, Thalidomide, Ubiquitin-Protein Ligases
Nat Chem Biol
Date: Dec. 01, 2019
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