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The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia López-Millán, Belén Costales, Paula Gutiérrez-Agüera, Francisco Díaz de la Guardia, Rafael Roca Ho, Heleia Vinyoles, Meritxell Rubio Gayarre, Alba Safi, Rémi Castaño Cardoso, Julio Romecín, Paola Alejandra Ramírez Orellana, Manuel Anguita, Eduardo Jeremias, Irmela Zamora, Lurdes Rodríguez-Manzaneque, Juan Carlos Bueno, Clara Morís, Francisco Menéndez Bujan, Pablo AML EC-70124 multi-kinase inhibitor FLT3-ITD mutation FLT3 inhibitor AML preclinical mode Fundació Carreras Funding: We thank CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for institutional support. This research was funded by the Spanish Ministry of Economy and Competitiveness (RTC-2016-4603-1 in collaboration with Entrechem, PID2019-108160RBI00/AEI/10.13039/501100011033), the Interreg V-A program (POCTEFA) 2014-2020 (grant PRO-TEOblood EFA360/19), Health Canada (H4080-144541) and Deutsche Josep Carreras Leukämie Stiftung in collaboration with I.J. to P.M. (15R/2021). P.M. and M.R.-O. also acknowledge the support from ISCIII-RICORS within the Next Generation EU program (plan de recuperación, transformación y resiliencia). Additional funding was provided by Consejería de Salud y Familia (PI-0119-2019) to RDG, the Health Institute Carlos III (FIS PI20/00822), Asociación Española Contra el Cáncer (PRYGN211192BUEN) and Ministerio de Ciencia e Innovacion (PLE2021-007518 and PI20/00822) to C.B. M.V. was supported by Juan de la Cierva fellowship (IJCI-2017-33172). B.L.-M. was supported by the Asociación Española Contra el Cáncer (INVES20011LÓPE) and Consejería de Salud y Familia (PEER-0028-2020). We thank CERCA/Generalitat de Catalunya and Fundaci? Josep Carreras-Obra Social la Caixa for institutional support. This research was funded by the Spanish Ministry of Economy and Competitiveness (RTC-2016-4603-1 in collaboration with Entrechem, PID2019-108160RB-I00/AEI/10.13039/501100011033), the Interreg V-A program (POCTEFA) 2014?2020 (grant PRO-TEOblood EFA360/19), Health Canada (H4080-144541) and Deutsche Josep Carreras Leuk?mie Stiftung in collaboration with I.J. to P.M. (15R/2021). P.M. and M.R.-O. also acknowledge the support from ISCIII-RICORS within the Next Generation EU program (plan de recuperaci?n, transformaci?n y resiliencia). Additional funding was provided by Consejer?a de Salud y Familia (PI-0119-2019) to RDG, the Health Institute Carlos III (FIS PI20/00822), Asociaci?n Espa?ola Contra el C?ncer (PRYGN211192BUEN) and Ministerio de Ciencia e Innovacion (PLE2021-007518 and PI20/00822) to C.B. M.V. was supported by Juan de la Cierva fellowship (IJCI-2017-33172). B.L.-M. was supported by the Asociaci?n Espa?ola Contra el C?ncer (INVES20011L?PE) and Consejer?a de Salud y Familia (PEER-0028-2020). 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. 2022 Article https://ddd.uab.cat/record/270611 urn:10.3390/cancers14061593 urn:oai:ddd.uab.cat:270611 urn:scopus_id:85126533422 urn:articleid:20726694v14n6p1593 urn:pmid:35326743 urn:pmc-uid:8946166 urn:pmcid:PMC8946166 urn:oai:pubmedcentral.nih.gov:8946166 eng Instituto de Salud Carlos III PI20/00822 Agencia Estatal de Investigación PID2019-108160 Cancers ; Vol. 14 Núm. 6 (3-2 2022), p. 1593 open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/ application/pdf