Journal
NATURE MEDICINE
Volume 15, Issue 7, Pages 750-U8Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.1983
Keywords
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Funding
- Children's Cancer Foundation of Baltimore
- Go4theGoal Foundation
- Foundation of Denver
- Liddy Shriver Sarcoma Initiative
- Amschwand Sarcoma Cancer Foundation
- Burroughs-Wellcome Clinical Scientist Award
- US National Institutes of Health [R01CA138212, R01CA133662, P30 CA051008]
- Georgetown University Medical Center Drug Discovery Program
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Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. We therefore used surface plasmon resonance screening to identify compounds that bind EWS-FLI1 and might block its interaction with RHA. YK-4-279, a derivative of the lead compound from the screen, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.
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