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

Publication Type:

Journal Article

Authors:

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

Source:

Cell Chem Biol, Volume 32, Issue 2, p.352-362.e10 (2025)

Keywords:

Animals, Antineoplastic Agents, Aurora Kinase A, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Female, Humans, Mice, Mice, Nude, Molecular Structure, N-Myc Proto-Oncogene Protein, Neoplasms, Experimental, Neuroblastoma, Protein Kinase Inhibitors, Structure-Activity Relationship

Abstract:

<p>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 &quot;undruggable&quot; proteins that are reliant on accessory proteins for cellular stabilization.</p>

PDB: 
9BZG and 9BZL
Detector: 
EIGER
Beamline: 
24-ID-E