EC-70124 acts as dual FLT3 PIM inhibitor and exerts potent activity in acute myeloid leukemia

• Acute Myeloid Leukemia (AML) is the most common myeloid malignancy in adults, and Internal Tandem Duplication (ITD) or kinase domain mutation of FLT3 represent the most frequent genetic alteration, accounting for 30% of cases associated with poor disease outcome. On the other hand, PIM kinases play an important role in enhancing cell survival and suppressing apoptosis in hematopoietic cells, particularly PIM-1 and PIM-2 whose overexpression has been reported in AML blasts.
• EC-70124, is a potent kinase inhibitor, in AML it behaves as a dual inhibitor of the FLT3 and PIM signaling pathways and causes complete tumor regression in preclinical animal models of the disease, representing a potentail best-in-class treatment following the recent approval of Novartis midostaurin (Rydapt®).

The results of a collaborative research between EntreChem SL, the University of Oviedo and Hospital Universitario Central de Asturias, HUCA (Oviedo, Spain), focused on searching new strategies against Acute Myeloid Leukemia (AML), the most common myeloid malignancy in adults, have been published in the journal Molecular Cancer Therapeutics.

The research, focuses on preclinical models bearing FLT3 mutations, and its blocking by EC-70124, a multi-kinase inhibitor previously characterized in solid tumor models. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important targets in AML such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. Comparable results were also observed ex vivo, in AML blasts derived from patients and treated with the drug, with best results in FLT3-mutated blast than FLT3 wild type blast.

EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate sustained inhibition of FLT3-STAT5, Akt-mTOR-S6, and Pim-BAD pathways.

Primary metabolism studies indicate that EC-70124 seems stable, without significant degradation or appearance of metabolites, as opossed to midostaurin. Moreover, protein plasma binding—typically very high for kinase inhibitors and cited often as a potential source of clinical failure—shows 3-times higher free unbound fraction in EC-70124 than midostaurin, a potential benefit for the clinical translation of the drug.

EC-70124 in vivo, when dosed orally in a FLT3-ITD xenograft model (MV4-11), demonstrates high efficacy, reaching complete tumor regression, including 1/8 permanent cures after 1 treatment cycle. Moreover, EC-70124 demonstrates a higher efficacy than midostaurin slowing tumor growth in the FLT3wt xenograft model (MOLM-16), evidencing the benefits of dual PIM-FLT3 inhibition by EC-70124 beyond the FLT3 mutant tumor models.

In summary, these findings underscore the antileukemic activity and preclinical characterization of a multikinase inhibitor, EC-70124, based on its ability to interfere the complex oncogenic events activated in AML at several levels. Because treatments directed against single targets such as FLT3 have not demonstrated the expected effectiveness, the unique kinase inhibitor profile exhibited by EC-70124 makes it an ideal candidate for the treatment of AML, and future studies are warranted to evaluate its clinical efficacy.

For full details, see: Puente-Moncada N, et al, Inhibition of FLT3 and PIM Kinases by EC-70124 Exerts Potent Activity in Preclinical Models of Acute Myeloid Leukemia, Mol. Cancer. Ther. 2018; doi: 10.1158/1535-7163.MCT-17-0530.