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首页> 外文期刊>Cancer Cell >Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma
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Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma

机译：Aurora-A的小分子抑制剂诱导儿童神经母细胞瘤中N-Myc的蛋白酶体降解。

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摘要

Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.
机译：MYCN的扩增是人类神经内分泌肿瘤（包括神经母细胞瘤）中的一个驱动突变。临床上没有靶向N-Myc（由MYCN编码的蛋白质）的小分子。 N-Myc与Aurora-A激酶形成复合物，从而保护N-Myc免受蛋白酶体降解。尽管稳定N-Myc不需要Aurora-A的催化活性，但我们在这里显示了两种Aurora-A抑制剂MLN8054和MLN8237破坏Aurora-A / N-Myc复合物并促进N-Myc的降解Fbxw7泛素连接酶。 Aurora-A / N-Myc复合体的破坏抑制了N-Myc依赖性转录，这与MYCN驱动的神经母细胞瘤小鼠模型中的肿瘤消退和延长的生存期有关。我们得出结论，Aurora-A是使N-Myc不稳定成为可行治疗策略的可及靶标。

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