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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Linked publications & trials

Abstract

Alzehimer's Disease (AD) is a complex disease, sometimes inherited, that exhibits progressive and irreversible 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. During this period, the project team worked to further optimize a lead molecule towards favorable physical properties, including crossing the blood-brain-barrier to reach the brain. The new analogs proved to have improved physical properties and potency against c-Abl kinase. The pharmacokinetics of the lead molecules were studied in detail, and were scaled up for long-term efficacy studies in diseased AD mice to track the cognitive effect and investigate the mechanism(s) of neuroprotection.