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Discovery and Development of Small Molecules That Reduce PNC Prevalence.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.


The perinucleolar compartment (PNC) is a subnuclear body found at the periphery of the nucleolus in the nucleus. Its function is not completely known yet, but it is a highly dynamic body that is enriched with Ribonucleic acid (RNA) transcripts and RNA-binding proteins. This compartment is highly prevalent in metastatic tumors and metastatically transformed cancer cell lines, making it a potential pan marker for metastatic progression. A high throughput, high content assay was developed to identify novel small molecules that reduce the prevalence of this metastasis biomarker in cancer cells. We have identified and further optimized a potent pyrrolopyrimidine series that reduces PNC prevalence in PC3M cells at submicromolar concentrations, where the cell viability is not affected. These compounds also show dose-dependent inhibition of migration and anchorage-independent growth in invasion and soft-agar assays, respectively. The probe candidate, ML246, has drug-like physical properties and displays promising protein kinase, making it an ideal in vivo tool for establishing the link between the PNC and the metastatic transformation of tumor cells. ML246 will serve as a pivotal first step to further research the function of the PNC and its role in cancer metastasis.

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