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: Aurora kinase; Aurora inhibitor; Aurora B kinase; Aurora A kinase; N-Myc

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