@misc{10481/74209,
year = {2022},
month = {3},
url = {http://hdl.handle.net/10481/74209},
abstract = {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.},
organization = {Asociación Española Contra el Cáncer
	INVES20011LÓPE, PEER-0028-2020},
organization = {Consejería de Salud y Familia
	PI-0119-2019},
organization = {Generalitat de Catalunya and Fundació Josep Carreras},
organization = {ISCIII-RICORS},
organization = {Juan de la Cierva fellowship
	IJCI-2017-33172},
organization = {Ministerio de Ciencia e Innovacion
	PI20/00822, PLE2021-007518},
organization = {Interreg
EFA360/19},
organization = {Centres de Recerca de Catalunya},
organization = {Health Canada

H4080-144541},
organization = {Ministerio de Economía y Competitividad

PID2019-108160RBI00/AEI/10.13039/501100011033, RTC-2016-4603-1},
organization = {Instituto de Salud Carlos III

FIS PI20/00822},
organization = {José Carreras Leukämie-Stiftung

15R/2021},
publisher = {MDPI},
keywords = {Acute myeloid leukemia},
keywords = {EC-70124 multi-kinase inhibitor},
keywords = {FLT3-ITD mutation},
keywords = {FLT3 inhibitor},
keywords = {AML preclinical model},
title = {The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia},
doi = {10.3390/cancers14061593},
author = {López Millán, María Belén and Díaz de la Guardia Quiles, Rafael and Rodríguez-Manzaneque, Juan Carlos},
}