Abstract
Myelodysplastic syndromes (MDS) are hematological disorders associated with bone marrow failure and abnormal hematopoietic cell growth, often progressing to acute myeloid leukemia (AML). Current treatments for AML and high-risk MDS are limited in efficacy, highlighting the need for new therapies. Recent studies show ferroptosis induction, alone or with standard chemotherapy, as a promising strategy for treating MDS/AML cells. Here, we report two novel compounds, HA344 and #231, that target both ferroptosis and apoptosis pathways to effectively eradicate MDS/AML cell lines and patient-derived bone-marrow blasts. RNASeq analysis reveals oxidative stress and apoptosis as key pathways activated by these compounds in different AML cell lines. In cellulo click-chemistry experiments coupled to mass spectrometry analysis identified glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) as primary targets of both compounds, inhibiting GPX4 and TXNRD1 in the micromolar range. Mass spectrometry analysis confirms that HA344 and #231 covalently bind GPX4; with however a higher affinity for selenium-containing GPX4 (GPX4-Se) than for sulfur-containing GPX4 (GPX4-S). These findings design HA344 and #231 as potential therapeutic options for MDS/AML treatment.