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

  • Nat Med. 2009 Jul;15(7):750-6. doi: 10.1038/nm.1983.
Hayriye V Erkizan  1 ,  Yali Kong ,  Melinda Merchant ,  Silke Schlottmann ,  Julie S Barber-Rotenberg ,  Linshan Yuan ,  Ogan D Abaan ,  Tsu-Hang Chou ,  Sivanesan Dakshanamurthy ,  Milton L Brown ,  Aykut Uren ,  Jeffrey A Toretsky
Affiliations
  • 1. Georgetown University, Lombardi Comprehensive Cancer Center, Department of Oncology, Washington, DC, USA.
PMID: 19584866 DOI: 10.1038/nm.1983
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.

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