TY - JOUR
T1 - PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase
AU - Adhikari, Bikash
AU - Bozilovic, Jelena
AU - Diebold, Mathias
AU - Schwarz, Jessica Denise
AU - Hofstetter, Julia
AU - Schröder, Martin
AU - Wanior, Marek
AU - Narain, Ashwin
AU - Vogt, Markus
AU - Dudvarski Stankovic, Nevenka
AU - Baluapuri, Apoorva
AU - Schönemann, Lars
AU - Eing, Lorenz
AU - Bhandare, Pranjali
AU - Kuster, Bernhard
AU - Schlosser, Andreas
AU - Heinzlmeir, Stephanie
AU - Sotriffer, Christoph
AU - Knapp, Stefan
AU - Wolf, Elmar
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
UR - http://www.scopus.com/inward/record.url?scp=85091614228&partnerID=8YFLogxK
U2 - 10.1038/s41589-020-00652-y
DO - 10.1038/s41589-020-00652-y
M3 - Article
C2 - 32989298
AN - SCOPUS:85091614228
SN - 1552-4450
VL - 16
SP - 1179
EP - 1188
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 11
ER -
