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Article Abstract
In neuroblastoma, 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 -amplified neuroblastoma, we designed PROTACs capable of degrading both Aurora-A and Aurora-B. Dual-degrading PROTACs and potently degraded Aurora-A (DC = 59 nM and 8.8 nM, respectively) and Aurora-B (DC = 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 -amplified IMR32 neuroblastoma cells. Global proteomics screening revealed that while demonstrated good selectivity, downregulated additional targets including threonine tyrosine kinase (TTK). Interestingly, TKK is also associated with -amplified neuroblastoma, and multi-target PROTAC reduced the viability of neuroblastoma IMR32 cells by 55% at 24 hours. The development of and generates new modalities for inhibiting the oncogenic activities of Aurora-A, Aurora-B, N-Myc, and TTK in neuroblastoma and other cancers.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331210 | PMC |
| http://dx.doi.org/10.1002/cmdc.202400703 | DOI Listing |
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