Targeted protein degradation reveals non-catalytic function of Aurora A kinase
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ABSTRACT:
PROVIDER: PRJNA595152 | ENA |
REPOSITORIES: ENA
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Project description:The mitotic kinase Aurora-A is essential for cell cycle progression and considered a priority cancer target. Dozens of ongoing clinical trials are testing the anti-cancer potential of Aurora-A kinase inhibitors. While the catalytic activity of Aurora-A is essential for its function during mitosis, a growing body of evidence indicates an additional non-catalytic function, which is difficult to target by kinase inhibitors. We therefor developed a series of degrader molecules by connecting a kinase inhibitor of Aurora-A to the Cereblon-binding molecule thalidomide. One degrader, JB170, induced the rapid degradation of Aurora-A. We were able to show that JB170 mediated depletion is highly specific for Aurora-A, as degrader mediated complex formation is supported by cooperative binding between Cereblon and Aurora-A. Strikingly, JB-170 mediated depletion caused a strong S-phase arrest, which is not the cell cycle effect observed as a result of Aurora-A kinase inhibition, supporting an important non-catalytic role of Aurora-A during DNA replication. Finally, depletion of Aurora-A resulted in strong induction of apoptosis in various cancer cell lines. The tool compound JB170 presents a versatile starting point for developing new therapeutic drugs to counter Aurora-A function in cancer. In the presented datasets, we determined i) the binding selectivity profile of the Aurora-A PROTAC (JB170) using Kinobeads affinity matrix and ii) its intracellular degradation specificity. We therefore treated IMR5 cells with JB170, the inactive version JB211, or Alisertib and quantified the induced degradation using tandem mass tags.
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Project description: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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Project description:Cutaneous T-cell lymphomas form a heterogeneous group of non-Hodgkin lymphomas characterized by only poor prognosis in advanced stage. Despite significant progress made in the identification of novel genes and pathways involved in the pathogenesis of cutaneous lymphoma, the therapeutic value of these findings has still to be proven. Here, we demonstrate by gene expression arrays that aurora kinase A is one of highly overexpressed genes of the serine/threonine kinase in CTCL. The finding was confirmed by qualitative RT-PCR, Western blotting and immunohistochemistry in CTCL cell lines and primary patient samples. Moreover, treatment with a specific aurora kinase A inhibitor blocks cell proliferation by inducing cell cycle arrest in G2 phase as well as apoptosis in CTCL cell lines. These new data provide a promising rationale for using aurora kinase A inhibition as a therapeutic modality of CTCL.
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