Anti-tumor activity of TAK-659, a dual inhibitor of SYK and FLT-3 kinases, in AML models.

e14091 Background: TAK-659 is a reversible, dual inhibitor of SYK and FLT-3 being developed for oncology indications including Acute Myelogenous Leukemia (AML), a disease driven by SYK and/or FLT-3-mediated signaling. Loss of SYK in AML cell lines has been shown to induce myeloid differentiation. FLT-3 is a Class III receptor tyrosine kinase that is normally expressed only in hematopoietic stem and progenitor cells. However, its expression has been found in the blasts of a majority of patients with AML. Activating mutations of FLT-3, including internal tandem duplication (ITDs) within the juxtamembrane region of FLT-3 and point mutations in the FLT-3 activation loop, are observed in approximately 30% of AML patients. These FLT-3 mutations, associated with early relapse and poor survival, represent a critical prognostic factor for AML. Methods: TAK-659 is an investigational inhibitor of SYK and FLT-3 that is currently being evaluated in a Phase 1b/2 clinical trial of AML patients (NCT02323113). TAK-659 inhibits purified SYK and FLT-3 enzymes with concentrations producing 50% inhibition (IC50) of 4.3 and 4.6 nM, respectively. In cultured human tumor cells, TAK-659 potently inhibited the growth of hematopoietic-derived cell lines, with a concentration producing half-maximal response (EC50) ranging from 11 to 775 nM in sensitive cell systems (eg, diffuse large B-cell lymphoma, and AML). In a broad kinase panel, TAK-659 demonstrated a more than 50-fold selectivity for SYK and FLT-3 over 290 other protein kinases. Results: Daily oral administration of 60 mg/kg TAK-659 showed anti-tumor activity in AML cell-line xenograft models representing FLT-3-ITD (MV-4-11 (TGI 96%)), and WT FLT-3 (KG-1 (TGI 66%)). The time course of pSYK (pSYK525) and pFLT3 (pFLT3591) expression were assessed following a single dose of TAK-659. Time dependent inhibition of these phospho-proteins, and an increase in cleaved caspase 3 expression, was observed in the AML models studied here. TAK-659 treatment of primary AML patient blasts using Vivia's ExviTech platform also revealed inhibition of cell proliferation and increase in cell death. Conclusions: Taken together these data support the clinical investigation of TAK-659 in the treatment of AML.