SMALL-MOLECULE INHIBITORS OF GATA2 AS A NOVEL THERAPEUTIC APPROACH FOR THERAPY-RESISTANT ACUTE MYELOID LEUKAEMIA

Acute myeloid leukaemia (AML) is an aggressive malignancy of the blood and bone marrow, characterised by the rapid proliferation of immature and dysfunctional white blood cells. Current AML therapies are largely non-specific and toxic, as they target both malignant and healthy cells, often leading to severe side effects and frequent relapse. AML is sustained by a population of leukaemia stem cells (LSCs), which are highly resistant to conventional chemotherapy and considered to be the main drivers of disease persistence and recurrence. Among the transcription factors regulating haematopoietic stem cell (HSC) differentiation, GATA2 plays a crucial role in maintaining self-renewal and proliferation. Its aberrant overexpression in LSCs, observed in nearly half of cytogenetically normal AML cases, has been shown to promote leukemogenesis and confer chemoresistance. Consequently, selective inhibition of GATA2 represents a promising therapeutic strategy, with the potential to eradicate pathogenic LSCs while sparing normal haematopoiesis. Through a structure-based virtual screening (SBVS) approach, an initial hit compound, CF-620, was identified as a potential inhibitor of GATA2. CF-620 features a hydantoin core structure bearing a 1H-indol-3-ylmethyl substituent at position 5 and an N-(naphthyl)-acetamide at position 3. Building upon this scaffold, the aim of this project, carried out in the laboratory of Dr. Marcella Bassetto (Cardiff University, UK) within the Erasmus+ programme, was to conduct a structure–activity relationship (SAR) study, to identify functional groups essential for biological activity. Two series of derivatives were designed: the first one to isolate and evaluate the stereochemically defined enantiomers of the indol-3-ylmethyl moiety, and the second one to replace the N-naphthyl-acetamide group with variously substituted aromatic rings. Overall, nineteen novel compounds were synthesised, enabling the assignment of the active enantiomer of the hit compound CF-620, and the identification of two new compounds more potent than the hit compound. These analogues represent the first step towards the development of selective GATA2 inhibitors, which may ultimately provide innovative therapeutic agents for AML treatment.