RT Journal Article
T1 The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia.
A1 Lopez-Millan, Belen
A1 Costales, Paula
A1 Gutiérrez-Agüera, Francisco
A1 Díaz de la Guardia, Rafael
A1 Roca-Ho, Heleia
A1 Vinyoles, Meritxell
A1 Rubio-Gayarre, Alba
A1 Safi, Rémi
A1 Castaño, Julio
A1 Romecín, Paola Alejandra
A1 Ramírez-Orellana, Manuel
A1 Anguita, Eduardo
A1 Jeremias, Irmela
A1 Zamora, Lurdes
A1 Rodríguez-Manzaneque, Juan Carlos
A1 Bueno, Clara
A1 Morís, Francisco
A1 Menendez, Pablo
K1 AML
K1 AML preclinical model
K1 EC-70124 multi-kinase inhibitor
K1 FLT3 inhibitor
K1 FLT3-ITD mutation
AB 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.
SN 2072-6694
YR 2022
FD 2022-03-21
LK http://hdl.handle.net/10668/20880
UL http://hdl.handle.net/10668/20880
LA en
DS RISalud
RD Apr 19, 2025