In silico and in vitro study of FLT3 inhibitors and their application in acute myeloid leukemia
Abstract
Acute myeloid leukemia (AML) is the most common hematological cancer in the adult population worldwide.Approximately 35% of patients with AML present internal tandem duplication (ITD) mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor associated with poor prognosis, and thus, this receptor is a relevant target for potential therapeutics.Tyrosine kinase inhibitors (TKIs) are used to treat AML; however, their molecular interactions and effects on leukemic cells are poorly understood.The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild-type (WT)-FLT3 and ITD-mutated (ITD-FLT3) structural models of FLT3, in its inactive aspartic acid-phenylalanine-glycine motif (DFG-out) and active aspartic acid-phenylalanine-glycine motif (DFG-in) conformations.Furthermore, the present study evaluated the effects of the second-generation TKIs gilteritinib and quizartinib on cancer cell viability, apoptosis and proliferation in the MV4-11 (ITD-FLT3) and HL60 (WT-FLT3) AML cell lines.Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were included as an FLT3-negative group.Molecular docking analysis indicated higher affinities of second-generation TKIs for WT-FLT3/DFG-out and WT-FLT3/DFG-in compared with those of the first-generation TKIs.However, the ITD mutation changed the affinity of all TKIs.The in vitro data supported the in silico…
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