Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway

摘要: Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine that, along with their ligands, the neurotrophins, involved in neuronal cell growth, development, survival. The Trk-neurotrophin pathway may also play a role tumorigenesis through oncogenic fusions, mutations, autocrine signaling, prompting development of novel Trk inhibitors as agents for cancer therapy. This report describes identification AZ-23, novel, potent, selective kinase inhibitor. In vitro studies AZ-23 showed improved selectivity over previous compounds inhibition activity cells at low nanomolar concentrations. vivo TrkA efficacy mice following oral administration TrkA-driven allograft model significant tumor growth Trk-expressing xenograft neuroblastoma. represents potent inhibitor from series potential use treatment cancer.