Boosting treatments for inflammatory diseases

The small molecule inhibitor MCC950 suppresses activation of a key process in inflammation involving inflammasomes and holds promise for the development of better treatments for inflammatory diseases.

Researchers from The University of Queensland and international collaborators developed the selective, small-molecule inhibitor MCC950 and found that it is a potent and specific blocker of the NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome.

Inflammasomes are large intracellular multiprotein complexes that play a central role in inflammation and have emerged as an attractive therapeutic target for reducing inflammation.

Aberrant activation of the NLRP3 inflammasome drives many autoinflammatory diseases, such as the inherited disorder cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis.

“Current therapies for inflammatory diseases, such as aspirin, ibuprofen and steroids, don’t work well in severe cases and are not targeted, which can limit their effectiveness and cause side effects,” said Dr Rebecca Coll, lead author of the study from UQ’s Institute for Molecular Bioscience.

“We now know that MCC950 can block an important component of the immune response - an inflammasome called NLRP3 that ‘switches on’ inflammation in our immune cells.”

MCC950 inhibited inflammatory responses in human cells by reducing interleukin-1b (IL-1b) production and it also reduced inflammation in mouse models of autoimmune and autoinflammatory disease.

These anti-inflammatory effects of MCC950 were not associated with inhibition of other components of the inflammasome complex that are important for control of infection.

This suggests that the compound may be used to treat myriad inflammatory diseases.

The researchers hope it can help treat patients with CAPS, a family of rare and severe autoinflammatory diseases caused by a genetic mutation to NLRP3.

The collaborative study involved seven institutions, including UQ, Trinity College Dublin, the National Human Genome Research Institute, the Walter and Eliza Hall Institute, and the Universities of Michigan, Massachusetts and Bonn.

The study has been published in Nature Medicine.