期刊
CANCERS
卷 14, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/cancers14061593
关键词
AML; EC-70124 multi-kinase inhibitor; FLT3-ITD mutation; FLT3 inhibitor; AML preclinical model
类别
资金
- Spanish Ministry of Economy and Competitiveness [RTC-2016-4603-1]
- Interreg V-A program (POCTEFA) 2014-2020 [PROTEOblood EFA360/19]
- Health Canada [H4080-144541]
- Deutsche Josep Carreras Leukamie Stiftung
- ISCIII-RICORS within the Next Generation EU program (plan de recuperacion, transformacion y resiliencia)
- Consejeria de Salud y Familia [PI-0119-2019, PEER-0028-2020]
- Health Institute Carlos III [FIS PI20/00822]
- Asociacion Espanola Contra el Cancer [PRYGN211192BUEN, INVES20011LOPE]
- Ministerio de Ciencia e Innovacion [PLE2021-007518, PI20/00822]
- Juan de la Cierva fellowship [IJCI-2017-33172]
- Entrechem [PID2019-108160RBI00/AEI/10.13039/501100011033]
- [15R/2021]
The study found that EC-70124 is a promising and safe agent for the treatment of FLT3-ITDMUT AML, exhibiting robust and specific antileukemia activity while sparing healthy hematopoietic cells.
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. 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.
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