Intracellular Activation of Dual-Pharmacophore Artezomib Enhances Selective Cytotoxicity in Hematologic Malignancies

We describe DQ-9, a dual-pharmacophore artezomib analogue that combines selective inhibition of immunoproteasome β5i with iron-dependent activation of artemisinin. DQ-9 exploits the elevated labile iron pool characteristic of hematologic malignancies, yielding selective cytotoxicity toward leukemia and multiple myeloma cells. DQ-9 affords sustained proteasome inhibition and induces oxidative stress and apoptosis through its iron-mediated activation and subsequent intracellular conversion to additional inhibitory species. In contrast, the deoxy analogue DQ-10, which lacks this activatable component, displays activity attributable solely to β5i inhibition, with correspondingly reduced cytotoxic potency. These findings establish iron-activable, β5i-targeting hybrids as a promising strategy to achieve enhanced selectivity and therapeutic efficacy against hematological malignancies.