A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma.
Cancer Res
; 84(6): 872-886, 2024 Mar 15.
Article
in En
| MEDLINE
| ID: mdl-38486486
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. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB. SIGNIFICANCE:
Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
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Benzbromarone
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Cerebellar Neoplasms
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Medulloblastoma
Limits:
Animals
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Child
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Humans
Language:
En
Journal:
Cancer Res
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Cancer res
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Cancer research
Year:
2024
Document type:
Article
Country of publication: