Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia

Abstract

BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with ΔT_m values exceeding 6 °C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC₅₀ values of 0.78 and 0.87 μM. Furthermore, 11r (0.5-10 μM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5-10 μM) concentration-dependently blocked cell cycle in MV4-11 cells at G₀/G₁ phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.

Keywords: 3-ethyl-benzo[d]isoxazole; BRD4 inhibitors; CDK6; acute myeloid leukemia; apoptosis; c-Myc.