PLK1 inhibitors show promise for inflammatory disease treatment, study shows

Molecule Social

A cancer drug in late-stage clinical trials could offer hope for the treatment of a wide range of inflammatory diseases, including gout and heart disease, say researchers.

University of Cambridge scientists have identified a molecule (PLK1) that plays a key role in triggering inflammation in response to materials the body sees as potentially harmful, report findings in the Journal of Clinical Investigation.

The research team says that PLK1 inhibitors that work by dampening the inflammatory response and have already passed through safety trials for cancer should now be tested against a range of other conditions.

Dr. Xuan Li, a co-author of the study from Cambridge University’s Department of Medicine, told there was a cluster of PLK1 inhibitor drugs developed for cancer treatment already in trials, including Volasertib (Boehringer Ingelheim, phases II and III), Onvansertib (Nerviano Medical Sciences, phase II), and GSK461364 (GSK, phase I).

“As Volasertib is already in a phase III trial, this one has been through safety [assessment],” she said.

The latest findings could potentially lead to new treatments for several inflammatory conditions in the near future, Li said.

Several conditions are characterized by overactivation of a component of the innate immune response known as an inflammasome -- specifically, the inflammasome NLRP3. Li and colleagues at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge have found that the PLK1 molecule helps NLRP3 respond. PLK1 helps organize tiny components of cells known as microtubule cytoskeletons, allowing important materials to be transported from one part of the cell to another.

“If we can get in the way of the microtubules as they try to organize themselves, then we can in effect slow down the inflammatory response, preventing it from causing collateral damage to the body. We believe this could be important in preventing a number of common diseases that can cause pain and disability and, in some cases, can lead to life-threatening complications,” Li said.

PLK1 is also widely studied for its role in mitosis -- a process which, when it goes awry, can lead to runaway cell division and the development of tumors. This has led to tests for drugs that inhibit its activity as potential treatments for cancer.

When Li and colleagues treated mice that had developed inflammatory diseases with a PLK1 inhibitor, they showed that it prevented the runaway inflammatory response, and at a much lower dose than would be required for cancer treatment. Inhibiting the molecule “calmed down’” NLRP3 in nondividing cells, preventing the overly aggressive inflammatory response seen in these conditions, according to the study.

“Taken together, our data not only unravel the mechanistic roles of PLK1 in regulating NLRP3 inflammasome activation but also propose a clinically available strategy for treating NLRP3-dependent inflammatory disorders," the authors wrote.

“Beyond the well-known role of PLK1 in controlling mitosis, we show that PLK1 plays a moonlighting role in interphase to control inflammation.”

The research was funded by the British Heart Foundation (BHF), a U.K. charity.

Professor James Leiper, BHF’s associate medical director said, “We hope that this research will open the door for new ways to treat people with heart diseases caused by overactive and aggressive immune responses, and look forward to more research to uncover how this drug could be repurposed.”

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