There are a lot of research eyes on the development of Polo-like kinase 1 (PLK1) inhibitors for cancer treatment right now, with several drugs currently in clinical trials and at least one in late-stage Phase III testing. But University of Cambridge scientists thought they’d try a different tack – using a PLK1 inhibitor to subdue a bad actor in inflammatory diseases – and, as they expected, it worked.
In the study, the researchers looked at the molecule NLRP3, which plays a pivotal role in tripping our innate immune system’s alarm in response to perceived dangerous foreign bodies, triggering inflammation to attack the microscopic intruders.
While this inflammasome is activated by a broad range of stimuli, it can also go into overdrive, which is at the root of many serious inflammatory diseases, including gout and heart failure.
In gout, a buildup of urate crystals in joints causes painful inflammation, and in heart attack, an accumulation of dead cells in the muscle triggers an aggressive innate immune response, which can worsen the already damaged organ.
Enter PLK1. This molecule is involved in a range of important cellular processes, but perhaps it is best known as a regulator of cell division (mitosis). PLK1 dysfunction in this process both promotes cancer growth and drastically accelerates it.
But another of its functions is playing a role in regulating the NLRP3 inflammasome – which is what the Cambridge researchers were most interested in. PLK1 also helps organize the microtubules cytoskeletons in our cells, which the scientists say act like train tracks to transport material within the cell.
In a mice study, the researchers found that a PLK1 inhibitor – the focus of the aforementioned cancer drug trials – could establish ‘roadblocks’ along that cellular track, to slow the inflammatory response, regulating the activity of and calming down NLRP3 in non-dividing cells.
“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,” said senior author of the study, Dr Xuan Li from the Department of Medicine at the University of Cambridge. “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."
The researchers are now planning to test the PLK1 inhibitor on inflammatory diseases in clinical trials.
"If we find that the drug is effective for these conditions, we could potentially see new treatments for gout and inflammatory heart diseases – as well as a number of other inflammatory conditions – in the not-too-distant future,” said Dr Li. "These drugs have already been through safety trials for cancer – and at higher doses than we think we would need – so we're optimistic that we can minimize delays in meeting clinical and regulatory milestones.”
The research was published in the Journal of Clinical Investigation.
Source: University of Cambridge
