Summary Paragraph MYCN amplification is the most frequent genetic driver in high-risk neuroblastoma (NB) and strongly associated with poor prognosis. 1,2 The N-Myc transcription factor, which is encoded by MYCN , is a mechanistically validated, yet challenging target for NB therapy development. 3,4 In normal neuronal progenitors, N-Myc undergoes rapid degradation, while in MYCN -amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. 5,6 Allosteric Aurora-A inhibitors that displace N-Myc from binding can promote N-Myc degradation, but with limited efficacy. 7–10 Here, we report a chemical approach to decrease N-Myc levels through the targeted protein degradation of Aurora-A. A first-in-class Aurora-A/N-Myc degrader, HLB-0532259 (compound 4 ), was developed from a novel Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of both Aurora-A and N-Myc with nanomolar potency and excellent selectivity and surpasses the cellular efficacy of established allosteric Aurora-A inhibitors. HLB-0532259 exhibits favorable pharmacokinetics properties and elicits tumor reduction in murine xenograft NB models. More broadly, this study delineates a novel strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.

Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders