2. Academic Validation
  3. A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma

A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma

  • Cancer Res. 2024 Mar 15;84(6):872-886. doi: 10.1158/0008-5472.CAN-22-3784.
Grace H Hwang 1 2,  Maria F Pazyra-Murphy 1 2,  Hyuk-Soo Seo 1 3,  Sirano Dhe-Paganon 1 3,  Sylwia A Stopka 4,  Marina DiPiazza 4,  Nizhoni Sutter 4 5,  Thomas W Gero 1,  Alison Volkert 1,  Lincoln Ombelets 1,  Georgia Dittemore 1,  Matthew G Rees 6,  Melissa M Ronan 6,  Jennifer A Roth 6,  Nathalie Y R Agar 1 4 7,  David A Scott 1 3,  Rosalind A Segal 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 5 Brigham Young University-Hawaii, Kulanui St, Hawaii.
  • 6 Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 7 Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
PMID: 38486486 DOI: 10.1158/0008-5472.CAN-22-3784
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-158059
    99.60%, EYA1 Antagonist