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- Title
A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma.
- Authors
Erkizan, Hayriye V.; Yali Kong; Merchant, Melinda; Schlottmann, Silke; Barber-Rotenberg, Julie S.; Linshan Yuan; Abaan, Ogan D.; Tsu-hang Chou; Dakshanamurthy, Sivanesan; Brown, Milton L.; Üren, Aykut; Toretsky, Jeffrey A.
- Abstract
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.
- Subjects
SARCOMA; RNA; ANTINEOPLASTIC agents; CELL death; TUMORS
- Publication
Nature Medicine, 2009, Vol 15, Issue 7, p750
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.1983