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

  • Cell Chem Biol. 2025 Jan 7:S2451-9456(24)00516-6. doi: 10.1016/j.chembiol.2024.12.006.
Jian Tang  1 ,  Ramkumar Moorthy  1 ,  Laura E Hirsch  1 ,  Özlem Demir  2 ,  Zachary D Baker  3 ,  Jordan A Naumann  4 ,  Katherine F M Jones  5 ,  Michael J Grillo  1 ,  Ella S Haefner  1 ,  Ke Shi  4 ,  Michaella J Levy  6 ,  Harshita B Gupta  7 ,  Hideki Aihara  4 ,  Reuben S Harris  8 ,  Rommie E Amaro  9 ,  Nicholas M Levinson  3 ,  Daniel A Harki  10
Affiliations
  • 1. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
  • 2. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3. Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
  • 4. Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
  • 5. Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
  • 6. KCAS Bioanalytical and Biomarker Services, Olathe, KS 66061, USA.
  • 7. Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
  • 8. Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA.
  • 9. Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
  • 10. Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].
PMID: 39778578 DOI: 10.1016/j.chembiol.2024.12.006
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.

Keywords
Aurora kinase A; MYCN; N-Myc; PROTAC; TPD; neuroblastoma; targeted protein degradation; transcription factor.
Products