Hall A P, Escott K J, Sanganee H, Hickling K C
Drug Safety & Metabolism Innovative Medicines, Macclesfield, Cheshire, England
Emerging Innovations, Scientific Partnering & Alliances, Macclesfield, Cheshire, England.
Toxicol Pathol. 2015 Apr;43(3):384-99. doi: 10.1177/0192623314544468. Epub 2014 Oct 16.
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.
AZD7969是糖原合酶激酶3（GSK3β）的强效抑制剂，GSK3β是一种多功能丝氨酸/苏氨酸激酶，对Wnt/β-连环蛋白信号通路起负调控作用。用AZD7969对大鼠和犬进行长达4周的治疗会导致一些变化，其中最显著的是许多组织中出现剂量依赖性且与治疗相关的增殖增加，这被认为是由于干细胞区室中Wnt/β-连环蛋白信号通路的去抑制所致。从表型上看这导致了增生，在胃肠道、肝脏、肾脏和肾上腺中增生维持了正常组织结构，而在骨骼、切牙和股胫关节中则破坏了正常组织结构。除了这些变化外，我们还注意到肝脏和近端小肠中铁负荷有与治疗相关的增加。这种脱靶效应强烈、有效，在犬和大鼠中均出现，这表明AZD7969可能是实验室研究铁储存障碍的一种有用的工具化合物。
