title: Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway.
abstract: Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer.
authors.affiliation: Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK. ken.thress@astrazeneca.com
authors.forename: Kenneth
authors.initials: K
authors.lastname: Thress
authors.forename: Terry
authors.initials: T
authors.lastname: Macintyre
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Dave
authors.initials: D
authors.lastname: Whitston
authors.forename: Zhong-Ying
authors.initials: ZY
authors.lastname: Liu
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffmann
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brown
authors.forename: Kevin
authors.initials: K
authors.lastname: Webster
authors.forename: Charles
authors.initials: C
authors.lastname: Omer
authors.forename: Peter E
authors.initials: PE
authors.lastname: Zage
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zeng
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D015375:Receptors, Interleukin-2 / Q000502:physiology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C544309:5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D015375:Receptors, Interleukin-2; D020917:Receptor, trkA