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

Fundació CarrerasFunding: 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