一种新型硫杂蒽酮激活p47phox以利用急性髓系白血病中的氧化还原脆弱性

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor outcomes, particularly among older adults and patients harboring adverse-risk features such as FLT3-ITD and p53 mutations. Relapsed or refractory (R/R) AML remains largely incurable, underscoring the urgent need for new therapies that selectively target leukemia-specific survival pathways while sparing normal hematopoiesis. Through a focused medicinal chemistry campaign, we optimized an understudied thioxanthenone chemotype and identified 06-30 as a potent lead compound with broad anti-AML activity. 06-30 induces robust and selective cytotoxicity across genetically diverse AML cell lines including models resistant to standard of care agents (cytarabine, azacitidine), and demonstrates strong activity in primary AML blasts with adverse molecular profiles. Unbiased integrative proteomic and transcriptomic analyses revealed p47phox (NCF1), a cytosolic organizer subunit of the NADPH oxidase complex, as the top common drug-induced target following 06-30 treatment with >9-fold increases in protein abundance and >50-fold increases in mRNA levels. Although p47phox is well established in host defense and inflammatory reactive oxygen species (ROS) generation, its role in AML pathogenesis and therapeutic sensitivity remains undefined. We hypothesize that p47phox functions as a pharmacodynamically regulated effector of 06-30 that drives ROS-mediated DNA damage and apoptosis in AML by exploiting leukemia-specific redox dysregulation. Supporting this hypothesis, shRNA-mediated silencing of p47phox significantly diminished 06-30-induced ROS generation and apoptosis and antioxidant co-treatment similarly blunted cell death. Importantly, 06-30 demonstrated selective toxicity toward AML cells while sparing normal CD34+ bone marrow progenitors, consistent with the enhanced antioxidant capacity of normal hematopoietic cells and establishing a clear therapeutic window. In vivo , 06-30 significantly extended overall survival and was very well tolerated. Ex vivo analyses demonstrated that its antileukemic efficacy was associated with increased p47phox expression and oxidative DNA damage as quantified by 8-oxoguanine levels. To our knowledge, no anticancer pharmacologic activators of p47phox have been previously described. Thus, thioxanthenone 06-30 represents both a first-in-class mechanistic probe and a promising therapeutic lead for redox-based targeting in AML. Together, these findings provide strong rationale for the further preclinical development and eventually clinical investigation of 06-30 as a strategy to exploit redox vulnerabilities in leukemia and improve outcomes for patients with limited therapeutic options.