Definition

An orally bioavailable inhibitor of three receptor tyrosine kinases: AXL (UFO), FMS-like tyrosine kinase-3 (Flt3; CD135; fetal liver kinase-2; Flk2), and the vascular endothelial growth factor receptor type 2 (VEGFR2), with potential anti-angiogenesis and antineoplastic activities. Upon oral administration, KC1036 targets, binds to and prevents the activation of AXL, FLT3 and VEGFR2. This blocks AXL, FLT3 and VEGFR2-mediated signal transduction pathways, and inhibits both AXL-, FLT3- and VEGFR2-mediated proliferation of tumor cells and the VEGFR2-mediated proliferation, survival and migration of endothelial cells. AXL, a member of the Tyro3, AXL and Mer (TAM) family of receptor tyrosine kinases, is overexpressed by many tumor cell types and also expressed in a variety of immune cells including macrophages, natural killer (NK) cells, and regulatory T cells (Tregs). It plays a key role in tumor cell proliferation, survival, invasion and metastasis, and is a mediator of immunosuppression. Its expression is associated with drug resistance and poor prognosis. FLT3, a class III tyrosine kinase receptor, is overexpressed or mutated in most B lineage and acute myeloid leukemias. VEGFR2 is frequently overexpressed by a variety of tumor types and tumor‐associated endothelial cells.