EPCT-17. DEVELOPING EYA PHOSPHATASE INHIBITORS WITH ON-TARGET EFFECTS IN SHH-MEDULLOBLASTOMA

Abstract Medulloblastoma, one of the most frequent malignant pediatric brain tumors, encompasses four molecularly and clinically distinct cancers. Sonic hedgehog (SHH)-subtype medulloblastoma constitutes about 30% of medulloblastomas, and therapies targeting the SHH pathway can lead to new highly selective treatment. The haloacid dehalogenase (HAD) phosphatase Eyes Absent 1 (EYA1) is critically involved in the development and progression of SHH-medulloblastoma: Eya1 is highly expressed in SHH-medulloblastomas, and single cell sequencing indicates that Eya1 is a consistent feature that can be detected in every individual cancer cell. Inhibition of EYA1 interrupts SHH pathway signaling. During normal development, EYA1 promotes symmetric division of cerebellar granule cell precursors (GCPs), the cells of origin for SHH-subtype medulloblastoma, and reduced levels of EYA1 decrease medulloblastoma mortality rates in mouse models. Therefore, targeting EYA1 may be a novel therapeutic avenue for these pediatric cancers. Benzarone derivatives have been suggested as allosteric EYA-inhibitors, and benzarone provides a promising platform for chemical derivatives. Here, we develop 60 novel benzarone derivatives and assess their efficacy in inhibiting SHH-medulloblastoma growth through the inhibition of EYA1. Several of the new compounds inhibit EYA1 phosphotyrosine phosphatase activity in a cell-based assay, interrupt SHH pathway, and prevent SHH-medulloblastoma growth in vitro. Our results show that these novel benzarone derivatives are a new promising avenue for developing therapeutics for pediatric SHH-medulloblastoma via inhibition of EYA phosphatases.