The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITD) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors hav...

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Detalles Bibliográficos
Autores: López-Millán, Belén|||0000-0002-9757-5454, Costales, Paula, Gutiérrez-Agüera, Francisco|||0000-0002-8620-2839, Díaz de la Guardia, Rafael|||0000-0001-9568-6719, Roca Ho, Heleia|||0000-0001-7324-5234, Vinyoles, Meritxell|||0000-0003-1906-4701, Rubio Gayarre, Alba, Safi, Rémi|||0000-0002-1697-872X, Castaño Cardoso, Julio|||0000-0002-0712-5856, Romecín, Paola Alejandra|||0000-0001-6890-5883, Ramírez, Manuel|||0000-0003-0332-6973, Anguita, Eduardo|||0000-0003-1386-4943, Jeremias, Irmela|||0000-0003-1773-7677, Zamora, Lurdes|||0000-0003-1713-7110, Rodríguez-Manzaneque, Juan Carlos|||0000-0001-5951-7029, Bueno, Clara|||0000-0003-1442-6216, Morís, Francisco, Menéndez Bujan, Pablo|||0000-0001-9372-1007
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270611
Acceso en línea:https://ddd.uab.cat/record/270611
https://dx.doi.org/urn:doi:10.3390/cancers14061593
Access Level:acceso abierto
Palabra clave:AML
EC-70124 multi-kinase inhibitor
FLT3-ITD mutation
FLT3 inhibitor
AML preclinical mode
Descripción
Sumario:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITD) 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-ITD AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITD 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-ITD 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-ITD 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-ITD.

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