Open AccessPROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase
Author(s) -
Bikash Adhikari,
Jelena Božilović,
Mathias Diebold,
Jessica Denise Schwarz,
Julia Hofstetter,
Martin Schröder,
Marek Wanior,
Ashwin Narain,
Markus Vogt,
Nevenka Dudvarski Stanković,
Apoorva Baluapuri,
Lars Schönemann,
Lorenz Eing,
Pranjali Bhandare,
Bernhard Küster,
Andreas Schlösser,
S. Heinzlmeir,
Christoph A. Sotriffer,
Stefan Knapp,
Elmar Wolf
Publication year - 2020
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-020-00652-y
Subject(s) - mitosis , aurora inhibitor , microbiology and biotechnology , aurora kinase , aurora a kinase , ubiquitin ligase , aurora b kinase , kinase , small molecule , cell cycle , chemistry , biology , cancer research , ubiquitin , apoptosis , biochemistry , cell , cell division , spindle apparatus , gene
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.