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Development of Dual Aurora-A and Aurora-B Degrading PROTACs for MCYN-Amplified Neuroblastoma

Sydney E Nelson1,2, James R Tucker1, Madelen G Prado1

  • 1Department of Chemistry and Biochemistry, Berry College, Mount Berry, GA 30149 (USA).

Chemmedchem
|August 11, 2025
PubMed

Insights

New dual-degrading PROTACs, dAurAB2 and dAurAB5, effectively reduce Aurora-A, Aurora-B, and N-Myc levels in neuroblastoma cells. These PROTACs show promise for treating MYCN-amplified neuroblastoma by targeting key oncogenic drivers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • MYCN amplification in neuroblastoma correlates with poor survival rates (<50%).
  • Overexpression of Aurora-A and Aurora-B kinases exacerbates neuroblastoma's oncogenic potential by stabilizing N-Myc.
  • Existing Aurora-A targeting proteolysis targeting chimeras (PROTACs) reduce Aurora-A and N-Myc but not Aurora-B.

Purpose of the Study:

  • To design and evaluate PROTACs capable of simultaneously degrading both Aurora-A and Aurora-B kinases.
  • To assess the efficacy of these dual-degrading PROTACs in MYCN-amplified neuroblastoma cells.
  • To investigate the impact of these PROTACs on N-Myc levels and overall neuroblastoma cell viability.

Main Methods:

  • Design and synthesis of dual-degrading PROTACs (dAurAB2 and dAurAB5) targeting Aurora-A and Aurora-B.
  • Treatment of MYCN-amplified IMR32 neuroblastoma cells with dAurAB2 and dAurAB5.
  • Quantification of Aurora-A, Aurora-B, and N-Myc protein levels via quantitative proteomics.
  • Assessment of cell viability and target selectivity through global proteomics screening.

Main Results:

  • dAurAB2 and dAurAB5 potently degraded Aurora-A and Aurora-B (e.g., DC50 for dAurAB5: Aurora-A 8.8 nM, Aurora-B 6.1 nM).
  • These PROTACs achieved 89%-97% degradation of Aurora-A and Aurora-B, reducing N-Myc levels by 38%-45%.
  • dAurAB5 demonstrated broader target engagement, downregulating threonine tyrosine kinase (TTK) and reducing IMR32 cell viability by 55%.

Conclusions:

  • Dual-targeting PROTACs dAurAB2 and dAurAB5 are effective in degrading Aurora-A, Aurora-B, and N-Myc in neuroblastoma.
  • dAurAB5's multi-target activity against Aurora kinases and TTK offers a promising therapeutic strategy for MYCN-amplified neuroblastoma.
  • These novel PROTACs represent a new class of inhibitors for treating neuroblastoma and potentially other cancers driven by these oncogenic pathways.
Keywords:
Aurora-AAurora-BN-MycPROTACneuroblastoma

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