Inflammasomes are a collection of large multiprotein structures responsible for the activation of inflammatory responses. There are six known inflammasome subtypes - NLRP1, NLRP3, NLRC4, NLRP6, AIM2 and IFI 16 - that respond to different stimuli. A primary function of the inflammasomes is to generate active caspase 1 from procaspase 1 in response to various pathogens and other stimuli. The ultimate products produced by the activation of caspase 1 are highly pro-inflammatory cytokines, IL-1β and IL-18. In addition, caspase 1 initiates pyroptosis, a highly inflammatory form of cell death, through the cleavage of gasdermin D. Excess IL-1β has been linked to a variety of diseases including rare genetic inflammatory diseases, cancer, liver and other gastrointestinal diseases, and cardiovascular diseases.
We believe caspase 1 occupies an important position in the IL-1β inflammatory cascade, controlling the production of IL-1β and initiation of pyroptotic cell death. Inhibition of caspase-1 provides a potential mechanism to block inflammation and reduce cell death by inhibiting pyroptosis. Currently, there are marketed biologic treatments directed at blocking IL-1β activity, but to our knowledge, there are no approved small molecules specifically targeted at reducing IL-1β activation. We believe an effective, oral caspase 1 inhibitor could have impact across a number of inflammasome-related diseases.