Identification of non-charged 7.44 analogs interacting with the NHR2 domain of RUNX1-ETO with improved antiproliferative effect in RUNX-ETO positive cells.

ABSTRACT: The RUNX1/ETO fusion protein is a chimeric transcription factor in acute myeloid leukemia (AML) created by chromosomal translocation t(8;21)(q22;q22). t(8;21) abnormality is associated with 12% of de novo AML cases and up to 40% in the AML subtype M2. Previously, we identified the small-molecule inhibitor 7.44, which interferes with NHR2 domain tetramerization of RUNX1/ETO, restores gene expression down-regulated by RUNX1/ETO, inhibits proliferation, and reduces RUNX1/ETO-related tumor growth in a mouse model. However, despite favorable properties, 7.44 is negatively charged at physiological pH and was predicted to have low to medium membrane permeability. Here, we identified M23, M27, and M10 as non-charged analogs of 7.44 using ligand-based virtual screening, in vivo hit identification,

SUBMITTER: Gopalswamy M 

PROVIDER: S-EPMC12095692 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature