Development of selective RAC1/KLRN inhibitors

Kalirin, named after the multidextrous Hindu goddess Kali for its ability to interact with multiple proteins, is a GEF (guanine nucleotide exchange factor) for the GTPase (enzyme hydrolyzing guanosine triphosphate to guanosine diphosphate) RAC1 that has been found to correlate with schizophrenia and Alzheimer’s Disease. Restoration of brain function through synaptic plasticity, the ability of neurons to modify the strength of their connections, offers much promise in the struggle against neurodegeneration. Kalirin contributes to synaptic plasticity through regulation of dendritic spine morphogenesis and actin cytoskeleton remodeling, both of which facilitate formation of new synapses. Therefore, developing kalirin selective inhibitors may give valuable insight into its function and possible effects on human health. We developed two novel compounds based on previous research on kalirin inhibitors. We partially confirmed the hypothesis that the in silico model’s accuracy in scoring novel chemical entities is a predictor of biological activity against the RAC1/kalirin target. We designed two novel compounds, we docked them in a computer model of the active site, we synthesized, and then tested their biological activity in an assay and compared against the model’s predictive score for binding to the active site. Compounds 3 and 4 had limited activity against RAC1/kalirin in a nucleotide exchange assay but gave useful insight into future structure-based design and development of kalirin selective inhibitors. Hence, we propose further structural modifications for the synthesis of more biologically potent and selective RAC1/kalirin inhibitors.