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The Science

Harnessing an Exciting New Target to Quench Inflammation

Pyroptosis and NETosis: Key Drivers of Inflammatory Disease

Pyroptosis and NETosis are two forms of inflammatory cell death that are triggered in response to various danger signals, including immune complexes, metabolic stresses and a variety of proteins recognized by damage associated molecular pattern (DAMP) receptors. Pyroptosis occurs in many cells, including inflammatory macrophages, and results in the release of proinflammatory cytokines and alarmins, which can in turn activate neighboring cells. A similar inflammatory form of cell death called NETosis occurs in neutrophils and results in the extrusion of neutrophil extracellular traps (NETs), in addition to the release of inflammatory cytokines and alarmins. While pyroptosis and NETosis evolved to activate innate immune responses against pathogens, aberrant and persistent activation of these pathways causes tissue damage and chronic inflammation underlying a range of severe inflammatory diseases.
Pyroptosis: Highly inflammatory programmed cell death characterized by cleavage of the pore-forming protein Gasdermin D.
NETosis: Neutrophil cell death characterized by secretion of large web-like structures called neutrophil extracellular traps (NETs) that are known to drive inflammation.

Gasdermin: An Exciting New Target in Inflammation

Gasdermin D was recently discovered as a central player in both pyroptosis and NETosis. Under normal cellular conditions, this intracellular protein remains in a full-length, inactive state. When pyroptosis or NETosis pathways are activated, Gasdermin D is cleaved by caspases or neutrophil elastase. The newly-freed N-terminal portion of Gasdermin D then oligomerizes to form a lytic pore across the cell membrane that allows release of inflammatory cytokines, alarmins, DNA and NETs. Pore formation can result in the cells being maintained in a hypersecretory state or progressing to lytic cell death and release of cellular contents to the extracellular environment.
When activated and cleaved, Gasdermin D oligomerizes to form a pore on the cell surface, causing the release of cellular contents. Many of these contents induce inflammation.
By inhibiting Gasdermin D, we can prevent pore formation and aberrant inflammation caused by multiple inflammatory cell death pathways.

New Opportunities, Broad Impact

While biologic drugs on the market target the inflammatory cytokine IL-1β, these drugs do not inhibit the activity of other inflammatory cytokines and alarmins that are released by dying cells. There are no marketed therapies specifically targeting inflammatory cell death. Inflammasome-targeting drugs are in development to selectively inhibit NLRP3, a key protein in the canonical inflammasome complex. However, these molecules differ from Gasdermin D inhibitors, as they do not inhibit the activity of other NLR, pyrin or AIM2 inflammasomes, nor do they inhibit the non-canonical inflammasome or NETosis cell death pathways.

The discovery of Gasdermin D provides the missing link that connects multiple inflammatory cell death pathways. Quench Bio recognizes the tremendous therapeutic opportunity at hand and is using orthogonal approaches to discover and develop small molecule inhibitors of Gasdermin D. Unlike other therapeutic approaches, targeting Gasdermin D affords us the ability to inhibit multiple inflammatory cell death pathways simultaneously. We believe that inhibiting Gasdermin D will lead to therapeutics with the potential to reduce inflammatory cytokines, alarmins and NETs, providing benefit to patients suffering from a range of inflammatory diseases.