Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization
Schanda J. et al.
RUNX1/ETO, the product of the t(8;21) chromosomal translocation, is required for the onset and maintenance of one of the most common forms of acute myeloid leukemia (AML). RUNX1/ETO has a modular structure and, besides the DN A-binding domain (Runt), contains four evolutionary conserved functional domains named nervy homology regions 1-4 (NHR1 to N HR4). The NHR domains serve as docking sites for a variety of different proteins and in addition the N HR2 domain mediates tetramerization through hydrophobic and ionic /polar interactions . Tetramerization is essential for RUNX1/ETO oncogenic activity. Destabilization of the RUNX1/ETO high molecular weight complex abrogates RUNX1/ETO oncogenic activity. Using a structure-based virtual screening, we identified several small molecule inhibitors mimicking the tetramerization hot spot within the NHR2 domain of RUNX1/ETO. One of these compounds, 7.44, was of particular interest as it showed biological activity in vitro and in vivo.
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