Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis

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.