Discovery of -(2-Acetamidobenzo[]thiazol-6-yl)-2-phenoxyacetamide Derivatives as Novel Potential BCR-ABL1 Inhibitors Through Structure-Based Virtual Screening.

BCR-ABL1 kinase is a critical driver of chronic myeloid leukemia (CML) pathophysiology. The approval of allosteric inhibitor asciminib brings new hope for overcoming drug resistance caused by mutations in the ATP-binding site. To expand the chemical diversity of BCR-ABL1 kinase inhibitors with positive anti-tumor effect with asciminib, structure-based virtual screening and molecular dynamics simulations were employed to discover novel scaffolds. This approach led to the identification of a series of -(2-acetamidobenzo[]thiazol-6-yl)-2-phenoxyacetamide derivatives as new BCR-ABL1 inhibitors. The most potent compound, , demonstrated inhibition of BCR-ABL-dependent signaling and showed an anti-tumor effect against K562 cells, with an IC value of 0.98 μM. Compound displayed powerful synergistic anti-proliferation and pro-apoptotic effects when combined with asciminib, highlighting its potential as a promising lead for the development of potential BCR-ABL inhibitors.