PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase.
Nat Chem Biol
; 16(11): 1179-1188, 2020 11.
Article
en En
| MEDLINE
| ID: mdl-32989298
ABSTRACT
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Talidomida
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Ubiquitina-Proteína Ligasas
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Inhibidores de Proteínas Quinasas
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Proteolisis
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Aurora Quinasa A
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Antineoplásicos
Límite:
Female
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Humans
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Male
Idioma:
En
Año:
2020
Tipo del documento:
Article