The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia López Millán, María Belén Díaz de la Guardia Quiles, Rafael Rodríguez-Manzaneque, Juan Carlos Acute myeloid leukemia EC-70124 multi-kinase inhibitor FLT3-ITD mutation FLT3 inhibitor AML preclinical model Simple Summary: Patients with AML harboring constitutively active mutations in the FLT3 receptor generally have a poor prognosis (FLT3-ITDMUT). Despite the fact that several FLT3 inhibitors have been developed, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin (a well-known FLT3 inhibitor). Our in vitro and in vivo experiments showed that EC-70124 exerts a robust and specific antileukemia activity against FLT3- ITDMUT AML cells while sparing healthy hematopoietic cells. Collectively, EC-70124 is a promising and safe agent for the treatment of this aggressive type of AML. 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 PROTEOblood 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). Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/cancers14061593/s1, Figure S1: Uncropped blots. 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. 2022-04-06T12:29:50Z 2022-04-06T12:29:50Z 2022-03-21 info:eu-repo/semantics/article Lopez-Millan, B.; Costales, P.; Gutiérrez-Agüera, F.; Díaz de la Guardia, R.; Roca-Ho, H.; Vinyoles, M.; Rubio-Gayarre, A.; Safi, R.; Castaño, J.; Romecín, P.A.; et al. The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia. Cancers 2022, 14, 1593. [https://doi.org/10.3390/cancers14061593] http://hdl.handle.net/10481/74209 10.3390/cancers14061593 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI