HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model.

Abstract
Ewing sarcoma is an aggressive tumor of bone and soft tissue affecting predominantly children and young adults. Tumor-specific chromosomal translocations create EWS-FLI1 and similar aberrant ETS fusion proteins that drive sarcoma development in patients. ETS family fusion proteins and over-expressed ETS proteins are also found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Transgenic expression of EWS-FLI1 in mice promotes high penetrance erythroid leukemia with dense hepatic and splenic infiltrations. We identified a small molecule, YK-4-279, that directly binds to EWS-FLI1 and inhibits its oncogenic activity in Ewing sarcoma cell lines and xenograft mouse models. Herein, we tested in vivo therapeutic efficacy and potential side effects of YK-4-279 in the transgenic mouse model with EWS-FLI1 induced leukemia. A two-week course of treatment with YK-4-279 significantly reduced white blood cell count, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly of erythroleukemic mice. YK-4-279 inhibited EWS-FLI1 target gene expression in neoplastic cells. Treated animals showed significantly better overall survival compared to control mice that rapidly succumbed to leukemia. YK-4-279 treated mice did not show overt toxicity in liver, spleen, or bone marrow. In conclusion, this in vivo study highlights the efficacy of YK-4-279 to treat EWS-FLI1 expressing neoplasms and support its therapeutic potential for patients with Ewing sarcoma and other ETS-driven malignancies.
AuthorsTsion Zewdu Minas, Jenny Han, Tahereh Javaheri, Sung-Hyeok Hong, Michaela Schlederer, Yasemin Saygideğer-Kont, Haydar Çelik, Kristina M Mueller, Idil Temel, Metin Özdemirli, Heinrich Kovar, Hayriye Verda Erkizan, Jeffrey Toretsky, Lukas Kenner, Richard Moriggl, Aykut Üren
JournalOncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37678-94 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
PMID26462019 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • EWS-FLI fusion protein
  • Indoles
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA, Messenger
  • RNA-Binding Protein EWS
  • YK 4-279
Topics
  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Disease Models, Animal
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Immunoenzyme Techniques
  • Indoles (pharmacology)
  • Leukemia, Erythroblastic, Acute (drug therapy, etiology, pathology)
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins, Fusion (administration & dosage, antagonists & inhibitors, toxicity)
  • Proto-Oncogene Protein c-fli-1 (administration & dosage, antagonists & inhibitors, toxicity)
  • RNA, Messenger (genetics)
  • RNA-Binding Protein EWS (administration & dosage, antagonists & inhibitors, toxicity)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Surface Plasmon Resonance

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: