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