title: Preclinical toxicity of AZD7969: Effects of GSK3β inhibition in adult stem cells.
abstract: AZD7969 is a potent inhibitor of glycogen synthase kinase 3 (GSK3β), which is a multifunctional serine/threonine kinase that negatively regulates the Wnt/β-catenin signaling pathway. Treatment of rats and dogs with AZD7969 for periods of up to 4 weeks resulted in a number of changes, the most significant of which was a dose-dependent, and treatment-related, increase in proliferation in a number of tissues that was thought to arise from derepression of Wnt/β-catenin signaling in the stem cell compartment. Phenotypically, this resulted in hyperplasia that either maintained normal tissue architecture in the gastrointestinal tract, liver, kidney, and adrenals or effaced normal tissue architecture within the bones, incisor teeth, and femorotibial joint. In addition to these changes, we noted a treatment-related increase in iron loading in the liver and proximal small intestines. This off-target effect was robust, potent, and occurred in both dogs and rats suggesting that AZD7969 might be a useful tool compound to study iron storage disorders in the laboratory.
authors.affiliation: Drug Safety & Metabolism Innovative Medicines, Macclesfield, Cheshire, England peter.a.hall@astrazeneca.com.
authors.forename: A P
authors.initials: AP
authors.lastname: Hall
authors.affiliation: Emerging Innovations, Scientific Partnering & Alliances, Macclesfield, Cheshire, England.
authors.forename: K J
authors.initials: KJ
authors.lastname: Escott
authors.affiliation: Emerging Innovations, Scientific Partnering & Alliances, Macclesfield, Cheshire, England.
authors.forename: H
authors.initials: H
authors.lastname: Sanganee
authors.affiliation: Drug Safety & Metabolism Innovative Medicines, Macclesfield, Cheshire, England.
authors.forename: K C
authors.initials: KC
authors.lastname: Hickling
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007501:Iron; D038362:Glycogen Synthase Kinase 3
keywords: AZD7969; GSK3b; glycogen synthase kinase 3β; safety assessment.; stem cell