Quantitative High-Throughput Screen for Compounds Blocking the Interaction Between CBF-beta and RUNX1 for the Treatment of Acute Myeloid Leukemia: Summary
Core Binding Factor (CBF) abnormalities are associated with 20-25% of all acute myeloid leukemias (AML), of which 5-10% are further sub classified as acute myelomonocytic leukemia with eosinophilia, also known as M4Eo in the FAB classification scheme. This subtype of leukemia is usually associated with chromosome 16 inversion (p13:q22). Chromosome 16 inversion results in formation of the fusion more ..
BioActive Compounds: 15
NCGC Assay Overview:
Core Binding Factor (CBF) abnormalities are associated with 20-25% of all acute myeloid leukemias (AML), of which 5-10% are further sub classified as acute myelomonocytic leukemia with eosinophilia, also known as M4Eo in the FAB classification scheme. This subtype of leukemia is usually associated with chromosome 16 inversion (p13:q22). Chromosome 16 inversion results in formation of the fusion oncogene CBFB-MYH11, which encodes the fusion protein CBF-beta-SMMHC. This fusion protein binds to RUNX1 (AML1) with high affinity and dominantly inhibits RUNX1 function preventing definitive hematopoiesis.
It has been hypothesized that the interference of CBF-beta and RUNX1 binding could have therapeutic implications for patients with CBF mediated leukemias. We developed a CBF-beta and RUNX1 binding assay in AlphaScreenTM format and optimized it for high throughput screening to search for inhibitors. The goal of this project is to screen MLPCN's compound collection (MLSMR) for identifying the inhibitors of the interaction between CBF-beta and RUNX1 proteins as research probes. If these probes work well in the animal models, the ultimate goal of this project is to development a new drug treatment for this disease.
This assay can not be used to assess how apparent inhibitors interfere with protein binding, and whether inhibitors specifically bind to either protein. Disruption of this protein-protein interaction, through any mechanism, is the intended target activity.
NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Production centers Network [MLPCN]
MLPCN Grant: X01MH083259-01
Assay Submitter (PI): Paul Liu
Please refer to all AIDs linked to this summary for detailed assay protocols for each assay.
MLSCN probes are given a score of 100. Molecules in the prior art are given a score of 80. Other, less active molecules in the same chemical series as the probe molecules are given a score of 50. Molecules pending validation are given a score of 10. Inactive analogues from these series are given a score of 0. The present results represent compounds with the largest PubChem score from AID 1477.
Categorized Comment - additional comments and annotations
Assay Type: Functional
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML223
PubChem Substance ID (SID) for probe 1: 109967254
PubChem Compound ID (CID) for probe 1: 60859
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 8600
Target for probe 1: CBFb::RUNX1
Disease relevance for probe 1: Leukemia
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133444/ (ID: 3026048)
Grant number for probe 1: MH083259-01
NCBI Book chapter title for probe 1: ML223: A Small Molecule Probe With In Vivo Activity Against Acute Myeloid Leukemia Subtype M4Eo
* Activity Concentration.
Data Table (Concise)