Transcriptomics

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Development of a benzarone derivative as targeted therapy for SHH-medulloblastoma [Day 5]


ABSTRACT: Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic hedgehog (SHH) signaling pathway. Eyes Absent (EYA1), a haloacid dehalogenase (HAD) phosphatase and co-transcription factor, is critical for tumorigenesis and proliferation of SHH-medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors for the Eya proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives, and identified one new compound, DS-1-38, that functions as an Eya-antagonist, opposes SHH-signaling, inhibits SHH-MB growth in vitro and in vivo, shows excellent brain penetrance and increases the lifespan of mice predisposed to fatal SHH-MB. Our data suggest that DS-1-38 provides a path for developing targeted therapeutic for pediatric SHH-MB.

ORGANISM(S): Mus musculus

PROVIDER: GSE229176 | GEO | 2023/12/21

REPOSITORIES: GEO

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