How polo kinases split cells

Scientists at the Universities of Manchester and Newcastle-upon-Tyne in the UK have discovered that a polo kinase enzyme (Cdc5p) interacts directly with the so-called transcription factor proteins that activate genes responsible for cell division.

"When the actions of enzymes like Polo kinase go unchecked, cells divide in an uncontrolled manner to form tumours. However, if we block their activity using chemical inhibitors the cells can no longer divide and the cancer cannot grow and spread, "​ said Professor Andrew Sharrocks, lead researcher in Manchester's Faculty of Life Sciences.

Unsurprisingly, many cancer therapies, both in development and out on the market, aim to control some aspect of cell replication. By fully understanding this particular mechanism of cell division, scientists could now develop more effective drugs or suggest different situations in which the drug could be used.

Polo kinases catalyse the reactions that enable a cell to divide by transferring phosphate groups to target proteins; in this case a protein called Ndd1p. This protein is part of a transcription factor complex and the researchers are the first to discover a direct link between a polo kinase and gene activation. If the polo kinase does not transfer the phosphate group to Ndd1p, cell division does not proceed properly.

Prof Sharrocks told DrugResearcher.com: "The cells do divide but are deformed. They will not grow and will eventually die."​

The work undertaken at Manchester and Newcastle has been completed on yeast proteins, a typical starting point for cell division research. Prof Sharrocks explained that the group are currently looking at finding the human analogue of Ndd1p to continue their research on mammalian systems, for example using polo-like kinase 1 (PLK-1).

It is not currently known why the phosphate is so important to this reaction. However, the team established where on Ndd1p the phosphate group is added to which will help in future research.

Prof Sharrocks said: "Kinase inhibitors are proving to be very effective at killing off rogue cells and trials on patients elsewhere have been promising with fewer toxic effects than current cancer treatments.​

"Our research on Polo kinase will help with this line of drug development and hopefully produce more effective kinase-blocking chemicals that will one day treat patients with different types of cancer."​

Despite the fact that it is only now that the full mechanism is understood, there are already several drugs in clinical trials that block polo kinases.

One such drug is Teva's IVX-214, which prevents the distribution of Polo-like kinase 1 (PLK-1). Pre-clinical studies have shown promising results and the company are planning Phase II trials in pancreas and prostate cancer. IVX-214 was discovered by Japanese company Nippon Shinyaku and was originally licensed and developed by Ivax Research.

There is also a great deal of research into aurora kinases, which are also involved in the cell cycle.

Merck and Vertex Pharmaceuticals have announced positive results for the Phase I clinical trials of MK-0457/VX-680. The drug inhibits several kinases including Aurora and BCR-ABL.

"Many patients with leukaemia develop resistance to standard anti-cancer therapies such as imatinib [Novartis' Gleevec/Glivec] because of a mutation of the disease,"​ said Dr Stephen Friend, executive vice president, oncology, Merck Research Laboratories.

"MK-0457 is the first compound to show clinical activity in patients with these treatment-resistant forms of blood cancer."​

Prof Sharrocks hopes the groundwork laid down by his team could help others develop drugs that target Polo kinases. These could prove more useful than aurora kinase therapies as they work earlier in the cell division pathway, he contends. The earlier a drug acts on a bodily process, the more far reaching its effects as downstream proteins (that could themselves be drug targets) are not produced.

The difficulty with such early pathway treatments is controlling their specificity.