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

Abstract

e14091Background: 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 inhi...