JB170

Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to its catalytic functions during mitosis and due to stabilization of the key oncoprotein MYCN.We report a small structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and both the 4- and 5-position as thalidomide exit vectors.PROTAC SK2188 induces the most potent AURKA degradation (DC50, 24h < 10 nM, Dmax, 1h 98%, Dmax, 24h, 80%) and significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids.Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and apoptosis.Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units.With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma.