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Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFβ interaction.

Abstract
Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes RUNX1 or CBFB, account for ~24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of ~50%. We hypothesize that the interaction between RUNX1 and CBFβ is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1-CBFβ interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBFβ directly, repress RUNX1/CBFB-dependent transactivation in reporter assays, and repress runx1-dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a RUNX1-ETO transgenic zebrafish, and reduced leukemia burden in a mouse CBFB-MYH11 leukemia model. Our data thus confirmed that RUNX1-CBFβ interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose.
AuthorsLea Cunningham, Steven Finckbeiner, R Katherine Hyde, Noel Southall, Juan Marugan, Venkat R K Yedavalli, Seameen Jean Dehdashti, William C Reinhold, Lemlem Alemu, Ling Zhao, Jing-Ruey Joanna Yeh, Raman Sood, Yves Pommier, Christopher P Austin, Kuan-Teh Jeang, Wei Zheng, Paul Liu
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 36 Pg. 14592-7 (Sep 4 2012) ISSN: 1091-6490 [Electronic] United States
PMID22912405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • Cbfb protein, mouse
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor beta Subunit
  • Runx1 protein, mouse
  • Benzodiazepines
Topics
  • Amino Acid Sequence
  • Animals
  • Benzodiazepines (pharmacology)
  • Blotting, Western
  • Core Binding Factor Alpha 2 Subunit (metabolism)
  • Core Binding Factor beta Subunit (genetics, metabolism)
  • Electrophoretic Mobility Shift Assay
  • Flow Cytometry
  • Fluorescence Resonance Energy Transfer (methods)
  • Genetic Vectors (genetics)
  • Hematopoiesis (drug effects)
  • High-Throughput Screening Assays (methods)
  • Histological Techniques
  • Humans
  • Immunoprecipitation
  • Jurkat Cells
  • Leukemia, Myeloid, Acute (genetics)
  • Mice
  • Molecular Sequence Data
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics)
  • Protein Interaction Mapping (methods)
  • Surface Plasmon Resonance
  • Transcriptional Activation (drug effects)
  • Zebrafish

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