Definition

An orally bioavailable inhibitor of the receptor tyrosine kinases AXL (UFO) and FMS-like tyrosine kinase-3 (FLT3; CD135; fetal liver kinase-2; Flk2), with potential antineoplastic activity. Upon oral administration, AXL/FLT3 inhibitor TT-00973 binds to and inhibits AXL and FLT3, including the FLT3-ITD-F691L gatekeeper mutation. Inhibition of these kinases leads to the disruption of downstream signaling pathways and the inhibition of cell growth of tumors in which these kinases are overexpressed or mutated. 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.