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New protein inhibitor impedes growth of cancerous cells

Researchers have developed a small-molecule inhibitor of a protein that plays key roles in the control of cell division, and they show that the inhibitor can halt the growth of tumors in mice and cancer-derived cells growing in culture. The findings are reported in companion papers reported by two collaborating groups—one (Lenart et al.) led by Jan-Michael Peters of the Research Institute of Molecular Pathology in Vienna, and the other (Steegmaier et al.) led by Norbert Kraut of Boehringer Ingelheim Austria GmbH. The papers will appear in Current Biology online on February 8th.

Because cancer cells are typically fast growing and can mutate to adapt to new growth conditions, effective drug-based therapies will likely succeed in part by impeding multiple functions required for cell division and survival. One particular class of proteins, known as kinases, is known to play especially critical roles in the division of healthy cells, and appears to also be important for cell division in cancer cells, even though these cells are diseased and have lost some of the restraints on division that normal cells impose on themselves. Because central aspects of cell division are under the control of just a few key kinases, these proteins represent potentially important targets for new cancer therapeutics, but few if any effective inhibitors have been identified as acting specifically and effectively against one particular cell-division kinase, known as Plk1.

In the new work, Steegmaier et al. isolated a chemical compound, which they term BI 2536, that they demonstrate to be a potent inhibitor of Plk1, and show that BI 2536 can indeed effectively halt the growth of cancerous cells, both in cell culture and in an animal model for human tumor growth. BI 2536 caused growth arrest and cell death in cell lines derived from a variety of human cancers, and it inhibited the growth of human tumor grafts in mice, resulting in the death of tumor cells and regression of large t umors. The authors report that BI 2536 has now been brought into use in clinical studies of patients with locally advanced or metastatic cancers in order to address the therapeutic potential of the compound.

In the companion paper, Lenart et al. use BI 2536 as a tool to probe the functions of Plk1 in normal cells. The availability of a specific Plk1 inhibitor is particularly useful in this regard because Plk1 is needed for a variety of different cellular processes required for cell division, and a chemical inhibitor such as BI 2536 allows Plk1 function to be experimentally disrupted at specific points during the cell-division cycle, thereby revealing the normal roles of Plk1 in new detail, and potentially identifying specific cellular processes that might be targeted by future anti-cancer therapeutics.
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Source:Cell Press


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