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Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genesRUNX1 orCBFB , 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, repressRUNX1/CBFB -dependent transactivation in reporter assays, and repressrunx1 -dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in aRUNX1–ETO transgenic zebrafish, and reduced leukemia burden in a mouseCBFB–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.

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