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

作者：Oo Zaw Min; Illendula Anuradha; Grembecka Jolanta; Schmidt Charles; Zhou Yunpeng; Esain Virginie; Kwan Wanda; Frost Isaura; North Trista E.; Rajewski Roger A.; Speck Nancy A.^*; Bushweller John H.^*

来源：Leukemia and Lymphoma, 2018, 59(9): 2188-2200.

DOI：10.1080/10428194.2017.1410882

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

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 CBF. 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.

• 出版日期2018