PuSH - Publikationsserver des Helmholtz Zentrums München: The multi-kinase inhibitor EC-70124 is a promising candidate for the treatment of FLT3-ITD-positive acute myeloid leukemia.

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Lopez-Millan, B.* ; Costales, P.* ; Gutiérrez-Agüera, F.* ; de la Guardia, R.D.* ; Roca-Ho, H.* ; Vinyoles, M.* ; Rubio-Gayarre, A.* ; Safi, R.* ; Castaño, J.* ; Romecín, P.A.* ; Ramírez-Orellana, M.* ; Anguita, E.* ; Jeremias, I. ; Zamora, L.* ; Rodríguez-Manzaneque, J.C.* ; Bueno, C.* ; Morís, F.* ; Menendez, P.*

The multi-kinase inhibitor EC-70124 is a promising candidate for the treatment of FLT3-ITD-positive acute myeloid leukemia.

Cancers 14:1593 (2022)

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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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