Progression of Metarrestin that Reduces PNC Prevalence and Elucidation of its Mechanism of Action

National Center For Advancing Translational Sciences

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Abstract

The collaborative team, through high-throughput screening followed by chemical optimization, developed a compound, metarrestin, which disrupts the perinuclear compartment (PNC) in different types of cancer cells. The PNC is a structure located within the nuclei of cancer cells and associated with metastatic capacity. Metarrestin inhibited tumor invasion and metastasis in multiple mouse models of cancer and prolonged the animals survival, suggesting its potential relevance for translation to patients. During this period, extensive studies using a variety of target deconvolution approaches led to the uncovering of potential targets and pathways for the compounds mechanism of action. The team has continued to investigate the mechanism of action of metarrestin using a set of in vitro and in vivo tools. New analogues have been generated through structure-activity relationship studies with the aim of avoiding brain penetration and potential neurotoxicity. These efforts will also help understand the complex nature of metastasis and its relation to the PNC.