Dapansutrile is a leader in the development of the NLRP3 antagonist class therapeutics that target the body’s first line of immunological response in the innate immune system. Dapansutrile inhibits NLRP3, the sensor molecule integral in the formation of the NLRP3 inflammasome.  Inflammasomes are multiprotein complexes involved in intracellular surveillance of danger signals that trigger an intense inflammatory response, via generation of bioactive IL-1β and IL-18 through caspase-1 activation.  By specific binding to NLRP3, dapansutrile prevents the formation of the NLRP3 inflammasome, which in turn inhibits the production of IL-1β and IL-18 as shown in Olatec’s publication Marchetti 2018a.

Role of NLRP3 and Interleukin-1 (IL-1) in the Pathogenesis of Disease
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NLRP3 (nucleotide-binding and oligomerization domain [NOD]-, leucine rich repeat-, pyrin domain-containing 3) is the primary sensor for inflammatory signals and integral in the production and release of active IL-1β.  The NLRP3 protein has a tripartite domain organization containing: 1) an amino-terminal death-fold domain (pyrin domain [PYD]); 2) a central NACHT nucleotide-binding domain; and 3) carboxy-terminal leucine-rich repeats. 

NLRP3 resides within cells and senses perturbations of cell homeostasis as well as intracellular danger in response to infectious stimuli or cellular stress NLRP3 activation leads to recruitment of ASC (or apoptosis speck-like protein containing a caspase recruiting domain), which consists of two death-fold domains: one pyrin domain and one caspase activation and recruitment domain (CARD).  ASC interacts with NLRP3 via PYD, which promotes assembly of the inflammasome.  Using its CARD domain, ASC brings monomers of pro‑caspase-1 into proximity fostering self-cleavage and formation of active caspase-1.  

Following inflammasome activation, caspase‑1 proteolytically cleaves precursors of IL‑1β and IL‑18 into their biologically active forms.  Once released, IL‑1b binds to the IL‑1 receptor type 1 (IL‑1R1) expressed on several cell types, leading to downstream signaling and a cascade of inflammation involving other pro-inflammatory cytokines, chemokines and several other mediators as shown in Dinarello 2011.

Production and release of active IL-1β, is a required mechanism in the natural response of the organism to infections and danger signals. However, when IL-1β becomes dysregulated, it becomes the contributing factor of many diseases, including: (1) diseases caused by metabolic dysfunction (e.g., heart failure, gout, diabetes mellitus, atherosclerosis), (2) diseases caused by the formation of crystals or aggregates (e.g., acute gout flare, Alzheimer’s disease, multiple sclerosis), and (3) fibrosis following either acute tissue injury or chronic inflammation (e.g., Acute Myocardial Infarction).

Breakthrough Technology
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Dapansutrile’s specific inhibition of the NLRP3 inflammasome represents an oral alternative and potentially safer option to biologic agents that target and neutralize processed IL‑1β and IL-18. As an orally administered NLRP3 inhibitor, dapansutrile has several unique therapeutic features. By inhibiting cytokine production at the level of the inflammasome instead of IL-1 signaling at the receptor, dapansutrile can mediate its effect without suppressing the function of other inflammasomes such as NLRP1, NLRC4, and AIM2, each critical to immune surveillance. Thus, unlike drugs which target the IL-1 receptor, dapansutrile does not completely abrogate IL-1 signaling.  Selective inhibition of NLRP3 by dapansutrile to date has not shown the immunosuppressive side effects and increased risk of infection observed following administration of certain anti-cytokine biologics (Salliot 2009; Galloway 2011).  Furthermore, an inhibitor of NLRP3 may offer greater therapeutic promise than just neutralizing IL-1β alone, as inhibiting inflammasome activation will also prevent caspase-1-mediated pyroptosis, a type of inflammatory cell death that causes release of more DAMPs (damage associated molecular patterns), which in turn induces more inflammation.

References
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1. Marchetti C, Swartzwelter B, Gamboni F, et al. OLT1177, a β-sulfonyl nitrile compound safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Nat Acad Sci. USA 2018a Feb 13;115(7):E1530-1539.
2. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011;117(14):3720-3732.
3. Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Annals of the Rheumatic Diseases2009;68:25-32.
4. Galloway JB, Hyrich KL, Mercer LK, et al. The risk of serious infections in patients receiving anakinra for rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register, Rheumatology2011;50(7):1341–1342.