Protein interacting with C kinase (PICK1) plays a role in the regulation of trafficking of AMPA receptors at neuronal synapses, via the specific interaction of its PDZ domain with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 protein-protein interaction has been shown to alter synaptic plasticity and dendritic spine density, but the lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring this as a therapeutic target for neurological diseases. Here, we report the discovery of potent small molecule PICK1 inhibitors using high throughput screening in combination with structure-based drug design. These inhibitors are the highest affinity small molecule PDZ domain inhibitors to date, and are shown to stabilize surface GluA2, to reduce Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and to block long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.

Discovery of potent small molecule inhibitors of the PICK1 PDZ-domain that modulate amyloid beta-mediated synaptic dysfunction

2019 Fall National Meeting

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