Abstract
Acute myeloid leukemia (AML) remains a challenging hematological malignancy due to its genetic heterogeneity, high relapse rates, and limited therapeutic options for refractory cases. FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations are among the most frequent genetic alterations in AML, associated with poor prognosis and treatment resistance. In this study, we investigated the antileukemic potential of compound HI042, identified from a library of 78 molecules, focusing on its effects on FLT3-ITD-mutated AML models. HI042 selectively reduced the viability of FLT3-ITD-positive cell lines, induced apoptosis, disrupted cell cycle progression, and diminished the clonogenic potential. Chemoinformatics analysis revealed structural similarities between HI042 and retinoic acid analogues, known for their differentiation-inducing effects. Consistently, HI042 treatments increased the level of differentiation markers, including CD11b and transcription factors such as PU.1 and C/EBPs, particularly in MOLM-13 cells. Furthermore, combining HI042 with the FLT3 inhibitor quizartinib synergistically enhanced apoptosis and reduced cell proliferation. These findings highlight HI042's dual activity in inducing differentiation and apoptosis while synergizing with established therapies. Overall, HI042 emerges as a promising candidate for targeted therapies against FLT3-ITD-mutated AML, addressing a critical need for novel treatment strategies for this high-risk AML subgroup.