%0 Journal Article
%A Lopez-Millan, Belen
%A Costales, Paula
%A Gutiérrez-Agüera, Francisco
%A Díaz de la Guardia, Rafael
%A Roca-Ho, Heleia
%A Vinyoles, Meritxell
%A Rubio-Gayarre, Alba
%A Safi, Rémi
%A Castaño, Julio
%A Romecín, Paola Alejandra
%A Ramírez-Orellana, Manuel
%A Anguita, Eduardo
%A Jeremias, Irmela
%A Zamora, Lurdes
%A Rodríguez-Manzaneque, Juan Carlos
%A Bueno, Clara
%A Morís, Francisco
%A Menendez, Pablo
%T The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia.
%D 2022
%@ 2072-6694
%U http://hdl.handle.net/10668/20880
%X Acute 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.
%K AML
%K AML preclinical model
%K EC-70124 multi-kinase inhibitor
%K FLT3 inhibitor
%K FLT3-ITD mutation
%~