OTHR-02. CHIMERIC AURORA A KINASE (AURKA) DEGRADERS EFFICIENTLY TARGET N-MYC

Abstract MYC family proteins are primary drivers of oncogenic processes in a variety cancer histologies. N-myc overexpression and amplification induce aggressive pediatric cancers, the most common which solid extracranial tumors children (neuroblastoma, NB) malignant CNS (medulloblastoma, MB). Due to addiction observed these tumor types, is considered an attractive therapeutic target. However, direct small molecule targeting remains technically challenging. Alternative approaches target this pathway include inhibiting thought stabilize N-myc, such as Aurora A kinase (AURKA). While inhibition AURKA was found be effective preclinical studies, no inhibitors have been approved for clinical use due lack efficacy. Here, we aim develop chimeric degrader molecules suitable that degrade concomitantly reduce levels. We used automated solid-phase synthesis generate library >1000 degraders using derivatives six known ligands (Series 1-6). limitations N-myc-driven MB cells vitro, employed NB proof-of-concept model. based on five showed efficient degradation, only series 3 6 could also diminish N-myc. Selected were further characterized pharmacokinetic pharmacodynamic experiments xenografts implanted flank CD1-nude mice. In summary, two individual efficiently degraded vitro vivo, providing foundation development novel therapies patients with cancers. Further studies will focus assessing antitumor properties lead candidates patient-derived orthotopic xenograft models.