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