A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells

Abstract

The core binding factor (CBF) gene RUNX1 is a target of chromosomal translocations in leukemia, including t(8;21) in acute myeloid leukemia (AML). Normal CBF function is essential for activity of AML1-ETO, product of the t(8;21), and for survival of several leukemias lacking RUNX1 mutations. Using virtual screening and optimization, we developed Runt domain inhibitors which bind to the Runt domain and disrupt its interaction with CBFβ. On-target activity was demonstrated by the Runt domain inhibitors’ ability to depress hematopoietic cell formation in zebrafish embryos, reduce growth and induce apoptosis of t(8;21) AML cell lines, and reduce progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. Runt domain inhibitors had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines. Our results confirmed that Runt domain inhibitors might prove efficacious in various AMLs and in T-ALL.

Keywords:

• Leukemia
• RUNX
• CBFB
• AML1-ETO
• TEL-AML1
• protein–protein interaction inhibitor
• PPI

Acknowledgements

The authors thank Martin Carroll and the University of Pennsylvania Stem Cell and Xenograft Core Facility for the AML cells, and for advice on culturing them.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1410882.

Additional information

Funding

Foundation for the National Institutes of Health (NIH) R01 CA108056 (J. H. B. and N. A. S.), R01 CA149976 (N. A. S.), R01 DK098241 (T. E. N.), and a Scholar Award from the Leukemia and Lymphoma Society (T. E. N.) supported this work.