Lopez-Millan, BelenCostales, PaulaGutiérrez-Agüera, FranciscoDíaz de la Guardia, RafaelRoca-Ho, HeleiaVinyoles, MeritxellRubio-Gayarre, AlbaSafi, RémiCastaño, JulioRomecín, Paola AlejandraRamírez-Orellana, ManuelAnguita, EduardoJeremias, IrmelaZamora, LurdesRodríguez-Manzaneque, Juan CarlosBueno, ClaraMorís, FranciscoMenendez, Pablo2023-05-032023-05-032022-03-212072-6694http://hdl.handle.net/10668/20880Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AMLAML preclinical modelEC-70124 multi-kinase inhibitorFLT3 inhibitorFLT3-ITD mutationresearch article35326743open access10.3390/cancers14061593PMC8946166https://www.mdpi.com/2072-6694/14/6/1593/pdf?version=1647867297https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946166/pdf