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.

有丝分裂激酶 AURORA-A 对细胞周期进程至关重要，被认为是优先的癌症靶点。尽管 AURORA-A 的催化活性对其有丝分裂功能至关重要，但最近的报告表明，它还具有额外的非催化功能，这是传统小分子难以靶向的。因此，我们通过将 AURORA-A 的临床激酶抑制剂与 E3 连接酶结合分子（例如沙利度胺）连接起来，开发了一系列化学降解剂 (PROTAC)。一种降解剂可诱导 AURORA-A 的快速、持久和高度特异性降解。此外，我们发现降解复合物通过 AURORA-A 和 CEREBLON 之间的协同结合而得到稳定。降解剂介导的 AURORA-A 消耗导致 S 期缺陷，这不是在激酶抑制时观察到的细胞周期效应，支持 AURORA-A 在 DNA 复制过程中的重要非催化功能。AURORA-A 降解诱导癌细胞系中的猖獗凋亡，因此代表了开发新疗法以对抗 AURORA-A 在癌症中的功能的通用起点。