A nuclear-targeted PROTAC enables subcellular-selective degradation of AURKA.

Aurora kinase A (AURKA) exerts its oncogenic effects partly through aberrant nuclear accumulation, thereby activating mechanisms that differ from its canonical cytoplasmic roles in cell cycle regulation. However, existing small molecule compounds, such as kinase inhibitors or degraders, are unable to selectively target nuclear AURKA. In this study, we developed a novel class of AURKA proteolysis targeting chimeras (PROTACs) that incorporate the UNC1215 warhead, which has been shown to recruit the nuclear L3MBTL3-DCAF5 E3 ligase complex in prior work. Through linker optimization, we synthesized a series of candidate degraders. Using an engineered cell model expressing exogenous nuclear or cytoplasmic AURKA, we identified a nuclear protein-specific targeting PROTAC, dnAurA-A10, which rapidly and selectively degrades nuclear AURKA. Based on the established subcellular specificity of AURKA functions, this study represents the first attempt to achieve subcellular degradation of pan-cellular oncoproteins using PROTACs, thereby providing a strategy and a chemical tool to directly probe AURKA's nuclear roles.