期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 11, 页码 1179-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-00652-y
关键词
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资金
- German Research Foundation [WO 2108/1-1, GRK 2243]
- European Research Council (TarMYC)
- Federal Ministry of Education and Research (CANCER)
- SGC, a registered charity from AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada [1097737]
- Innovative Medicines Initiative (EU/EFPIA) (EUbOPEN) [1097737, 875510]
- Janssen [1097737]
- Merck KGaA [1097737]
- MSD [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome Trust [1097737]
- Else Kroner-Fresenius PhD program (TRIP)
- German Cancer Research Center DKTK
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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