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

SIMPLE SUMMARY: Patients with AML harboring constitutively active mutations in the FLT3 receptor generally have a poor prognosis (FLT3-ITD(MUT)). 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-ITD(MUT). 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-ITD(MUT) 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. ABSTRACT: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITD(MUT)) 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(MUT) AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITD(MUT) 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(MUT) 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(MUT) 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(MUT).