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 goal of this project is to develop inhibitors of the perinuclear compartment (PNC), a sub-nuclear body that is prevalent in metastatic cancer cells, mostly of solid origin. Such compounds are predicted to have antimetastatic activity in tumor cells. These efforts will also help understand the complex nature of metastasis and its relation to the PNC. MOA studies will also probe critical pathways for metastatic transformation. During this period, the collaborative team, through high-throughput screening followed by chemical optimization, has 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. Extensive studies using a variety of target deconvolution approaches have led to the uncovering of potential targets and pathways for the compounds mechanism of action.