HTS to Identify Inhibitors of c-Abl kinase for the Potential Treatment of Alzheimer's Disease

National Center For Advancing Translational Sciences

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Abstract

Alzehimer's Disease (AD) is a complex disease, sometimes inherited, that progress with the age with an irreversible and progressive brain damage that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks of daily living. These losses are related to the breakdown of the connections between different classes of neurons in the brain and the eventual death of many of these cells. Although important progress has been made in the understanding on the development of AD, the basic biology, the factors that influence it and the identification of therapeutics targets, few therapies, treatment approaches and preventive strategies have been developed. Studies performed by members of the project team, at the Pontificia Universidad Catolica de Chile, showed that the c-Abl kinase is activated in neurons exposed to amyloid-beta and in in vivo AD animal models; rats exposed to amyloid-beta hippocampus injection and the transgenic APPsewPSEN1dE9 mice. The activation of c-Abl signalling was observed, with phosphorylation and induction of its p73 (the pro-apoptotic form) targets and cdk5 both in vitro and in vivo AD models, supporting the hypothesis that the c-Abl signalling participates in AD neuronal death and show that c-Abl inhibitors are useful to decrease the progression of the disease. During this period, the project team worked to further optimize a lead molecule towards favorable physical properties. The new analogs proved to have better physical properties as well as improved potency against c-Abl kinase. The pharmacokinetics of the lead molecules were also studied in detail, and were scaled up for long-term efficacy studies in diseased AD mice to track the cognitive effect of the lead molecule.