PUBLICATION
A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells
- Authors
- Oo, Z.M., Illendula, A., Grembecka, J., Schmidt, C., Zhou, Y., Esain, V., Kwan, W., Frost, I., North, T.E., Rajewski, R.A., Speck, N.A., Bushweller, J.H.
- ID
- ZDB-PUB-171219-11
- Date
- 2017
- Source
- Leukemia & lymphoma 59(9): 2188-2200 (Journal)
- Registered Authors
- North, Trista
- Keywords
- AML1-ETO, CBFB, Leukemia, PPI, RUNX, TEL-AML1, protein–protein interaction inhibitor
- MeSH Terms
-
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/metabolism*
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Core Binding Factor alpha Subunits/genetics
- Core Binding Factor alpha Subunits/metabolism*
- Core Binding Factor beta Subunit/genetics
- Core Binding Factor beta Subunit/metabolism*
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Mice
- Molecular Structure
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Protein Binding/drug effects
- Small Molecule Libraries/chemistry
- Small Molecule Libraries/metabolism*
- Small Molecule Libraries/pharmacology
- Translocation, Genetic
- Zebrafish
- PubMed
- 29249175 Full text @ Leuk. Lymphoma
Citation
Oo, Z.M., Illendula, A., Grembecka, J., Schmidt, C., Zhou, Y., Esain, V., Kwan, W., Frost, I., North, T.E., Rajewski, R.A., Speck, N.A., Bushweller, J.H. (2017) A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells. Leukemia & lymphoma. 59(9):2188-2200.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping