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

  • ChemMedChem. 2025 Mar 3;20(5):e202400703. doi: 10.1002/cmdc.202400703.
Sydney E Nelson  1  2 ,  James R Tucker  1 ,  Madelen G Prado  1 ,  Lillian C Tierney  1 ,  Sarah L Quigley  1 ,  Andrew T Lumpkin  1 ,  Cayden J Dodd  1 ,  Viola Hasko  1 ,  Savannah L Howie  1 ,  Aastha  2 ,  Britton K Ody  3 ,  Jun Yin  3 ,  Jennifer M Heemstra  2 ,  Mark Turlington  1
Affiliations
  • 1. Department of Chemistry and Biochemistry, Berry College, Mount Berry, GA 30149 (USA).
  • 2. Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130 (USA).
  • 3. Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303 (USA).
PMID: 40785977 DOI: 10.1002/cmdc.202400703
Abstract

In neuroblastoma, MCYN amplification is associated with survival rates of <50%. Overexpression of the mitotic kinases Aurora-A and Aurora-B are also associated with low survival and exacerbate the oncogenic effects of N-Myc. As N-Myc is stabilized by Aurora-A, Aurora-A targeting proteolysis targeting chimeras (PROTACs) have been developed that reduce Aurora-A and N-Myc levels. However, simultaneous degradation of N-Myc, Aurora-A, and Aurora-B has not been previously achieved. Given the contributions of both Aurora kinases to MYCN-amplified neuroblastoma, we designed PROTACs capable of degrading both Aurora-A and Aurora-B. Dual-degrading PROTACs dAurAB2 and dAurAB5 potently degraded Aurora-A (DC50 = 59 nM and 8.8 nM, respectively) and Aurora-B (DC50 = 39 nM and 6.1 nM), eliminated 89% - 97% of Aurora-A and Aurora-B, and reduced N-Myc levels by 38% and 45% in MCYN-amplified IMR32 neuroblastoma cells. Global proteomics screening revealed that while dAurAB2 demonstrated good selectivity, dAurAB5 downregulated additional targets including threonine tyrosine kinase (TTK). Interestingly, TKK is also associated with MCYN-amplified neuroblastoma, and multi-target PROTAC dAurAB5 reduced the viability of neuroblastoma IMR32 cells by 55% at 24 hours. The development of dAurAB2 and dAurAB5 generates new modalities for inhibiting the oncogenic activities of Aurora-A, Aurora-B, N-Myc, and TTK in neuroblastoma and Other cancers.

Keywords
Aurora-A; Aurora-B; N-Myc; PROTAC; neuroblastoma.
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