| First Author | Hwang GH | Year | 2024 |
| Journal | Cancer Res | Volume | 84 |
| Issue | 6 | Pages | 872-886 |
| PubMed ID | 38486486 | Mgi Jnum | J:346077 |
| Mgi Id | MGI:7612619 | Doi | 10.1158/0008-5472.CAN-22-3784 |
| Citation | Hwang GH, et al. (2024) A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma. Cancer Res 84(6):872-886 |
| abstractText | 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. |
