Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.

Therapeutic Approaches

Abstract

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

Authors

Frankowski, Kevin J; Wang, Chen; Patnaik, Samarjit; Schoenen, Frank J; Southall, Noel; Li, Dandan; Teper, Yaroslav; Sun, Wei; Kandela, Irawati; Hu, Deqing; Dextras, Christopher; Knotts, Zachary; Bian, Yansong; Norton, John; Titus, Steve; Lewandowska, Marzena A; Wen, Yiping; Farley, Katherine I; Griner, Lesley Mathews; Sultan, Jamey; Meng, Zhaojing; Zhou, Ming; Vilimas, Tomas; Powers, Astin S; Kozlov, Serguei; Nagashima, Kunio; Quadri, Humair S; Fang, Min; Long, Charles; Khanolkar, Ojus; Chen, Warren; Kang, Jinsol; Huang, Helen; Chow, Eric; Goldberg, Esthermanya; Feldman, Coral; Xi, Romi; Kim, Hye Rim; Sahagian, Gary; Baserga, Susan J; Mazar, Andrew; Ferrer-Alegre, Marc; Zheng, Wei; Shilatifard, Ali; Aubé, Jeffrey; Rudloff, Udo; Marugan, Juan Jose; Huang, Sui;

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