A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma.
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.
Erkizan
Hayriye V
HV
Georgetown University, Lombardi Comprehensive Cancer Center, Department of Oncology, Washington, DC, USA.
Kong
Yali
Y
Merchant
Melinda
M
Schlottmann
Silke
S
Barber-Rotenberg
Julie S
JS
Yuan
Linshan
L
Abaan
Ogan D
OD
Chou
Tsu-Hang
TH
Dakshanamurthy
Sivanesan
S
Brown
Milton L
ML
Uren
Aykut
A
Toretsky
Jeffrey A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors*; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C106031:EWS-FLI fusion protein; D007211:Indoles; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; C562345:YK 4-279; D053148:Caspase 3; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases