Development of Dual Aurora‐A and Aurora‐B Degrading PROTACs for MYCN‐Amplified Neuroblastoma

• DOI: 10.1002/cmdc.202400703
• Publication Date: 2024-11-21T03:13:41Z
• Authors: Sydney E. Nelson; James R. Tucker; Madelen G. Prado; Lillian C. Tierney; Sarah L. Quigley; Andrew T. Lumpkin; Cayden J. Dodd; Viola Hasko; Savannah L. Howie; Aastha; Britton K. Ody; Jun Yin; Jennifer M. Heemstra; Mark Turlington
• Keywords: 0301 basic medicine; 0303 health sciences

AbstractIn neuroblastoma, MYCN 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 MYCN‐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 MYCN‐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.