A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma Journal Article

Authors: Erkizan, H. V.; Kong, Y.; Merchant, M.; Schlottmann, S.; Barber-Rotenberg, J. S.; Yuan, L.; Abaan, O. D.; Chou, T.; Dakshanamurthy, S.; Brown, M. L.; Ren, A.; Toretsky, J. A.
Article Title: A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma
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. © 2009 Nature America, Inc. All rights reserved.
Keywords: controlled study; unclassified drug; human cell; nonhuman; antineoplastic agents; animal cell; mouse; animals; mice; cells, cultured; apoptosis; neoplasm proteins; animal experiment; caspase 3; tumor xenograft; xenograft model antitumor assays; cercopithecus aethiops; cos cells; transcription factors; ewing sarcoma; dead-box rna helicases; cancer inhibition; tumor cell; oncogene proteins, fusion; rna binding protein ews; rna helicase; rna helicase a; transcription factor fli 1; surface plasmon resonance; sarcoma, ewing's
Journal Title: Nature Medicine
Volume: 15
Issue: 7
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2009-07-01
Start Page: 750
End Page: 756
Language: English
DOI: 10.1038/nm.1983
PUBMED: 19584866
PROVIDER: scopus
PMCID: PMC2777681
Notes: --- - "Cited By (since 1996): 19" - "Export Date: 30 November 2010" - "CODEN: NAMEF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Tsu-Hang Chou
    2 Chou