Definition

An orally bioavailable inhibitor of multiple kinases, including the receptor tyrosine kinases AXL (UFO) and FMS-like tyrosine kinase-3 (FLT3; CD135; fetal liver kinase-2; Flk2), and the neurotrophic tyrosine receptor kinases (NTRKs), with potential antineoplastic activity. Upon oral administration, AXL/FLT3/NTRK inhibitor HH30134 binds to and inhibits wild-type, point mutants and fusion proteins of AXL, FLT3 and NTRK. 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, rearranged 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. TRK, a family of receptor tyrosine kinases (RTKs) activated by neurotrophins, is encoded by NTRK family genes. The expression of either mutated forms of, or fusion proteins involving, NTRK family members results in uncontrolled TRK signaling, which plays an important role in tumor cell growth, survival, invasion and treatment resistance.