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

Lea 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

Research output: Contribution to journalArticle

62 Scopus citations

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 amouse 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.

Original languageEnglish (US)
Pages (from-to)14592-14597
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number36
DOIs
StatePublished - Sep 4 2012

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    Cunningham, L., Finckbeiner, S., Hyde, R. K., Southall, N., Marugan, J., Yedavalli, V. R. K., Dehdashti, S. J., Reinhold, W. C., Alemu, L., Zhao, L., Yeh, J. R. J., Sood, R., Pommier, Y., Austin, C. P., Jeang, K. T., Zheng, W., & Liu, P. (2012). Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFβ interaction. Proceedings of the National Academy of Sciences of the United States of America, 109(36), 14592-14597. https://doi.org/10.1073/pnas.1200037109