Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Chemical Biology Pub Date : 2025-01-07 DOI:10.1016/j.chembiol.2024.12.006

Jian Tang, Ramkumar Moorthy, Laura E. Hirsch, Özlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F.M. Jones, Michael J. Grillo, Ella S. Haefner, Ke Shi, Michaella J. Levy, Harshita B. Gupta, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki

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Abstract

The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. 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. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.