Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway.
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.
Thress
Kenneth
K
Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK. ken.thress@astrazeneca.com
Macintyre
Terry
T
Wang
Haiyun
H
Whitston
Dave
D
Liu
Zhong-Ying
ZY
Hoffmann
Ethan
E
Wang
Tao
T
Brown
Jeffrey L
JL
Webster
Kevin
K
Omer
Charles
C
Zage
Peter E
PE
Zeng
Lizhi
L
Zweidler-McKay
Patrick A
PA
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
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