NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity[1]. Dapansutrile（OLT1177） is a potent, selective and orally active inhibitor of NLRP3 inflammasome. Anti-inflammatory, analgesic activity[2]. OLT1177 specifically inhibited both canonical and noncanonical NLRP3 inflammasome activation in vitro, and showed no effect on the AIM2 and NLRC4 inflammasomes. OLT1177 reduced caspase-1 activity and IL-1β production in monocytes from patients with CAPS and alleviated the severity of LPS-induced systemic inflammation in vivo. Importantly, no biochemical or hematological adverse effects were observed in humans receiving a high concentration of OLT1177 for 8 days. Like CY-09, OLT1177 exerts its anti-inflammatory effect on NLRP3 inflammasome activation independently of signal 1 (NLRP3 and pro-IL-1β expression) or K+ efflux,but directly binds to NLRP3 and inhibits ATPase activity[3]. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth[4].
Dapansutrile 细胞实验
Cell Line
Concentration
Treated Time
Description
References
human blood monocyte-derived macrophages
1 μM
inhibition of IL-1β secretion
Arthritis Res Ther. 2018 Aug 3;20(1):169
Mouse primary microglia cells
5 μM or 10 μM
24 h
To evaluate the effect of OLT1177 on the inflammatory response of LPS-stimulated microglia. Results showed that 5 μM OLT1177 significantly reduced the release of IL-1β, IL-6, and TNF-α.
Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32145-32154
Dapansutrile 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Cyclophosphamide-induced interstitial cystitis model
Oral gavage
100 mg/kg
Every other day until the experimental endpoint on day eight
Dapansutrile improved the pathology of cyclophosphamide-induced interstitial cystitis, reduced inflammation scores, decreased the frequency and number of mast cells and neutrophils, reduced T cell infiltration in the bladder, and lowered systemic proinflammatory cytokine levels.
Front Immunol. 2022 Jun 3;13:903834
C57BL/6 mice
Experimental autoimmune encephalomyelitis (EAE) model
Oral
3.75g/kg food
From the day of immunization induction, lasting for 23 days
To evaluate the therapeutic effects of OLT1177 in the EAE model. Results showed that oral OLT1177 significantly improved functional deficits and spinal cord demyelination in EAE mice, and reduced protein levels of IL-1β, IL-18, IL-6, and TNF-α in the spinal cord, as well as reduced infiltration of CD4 T cells and macrophages.
Front Immunol. 2019 Nov 1;10:2578
Male C57BL/6 mice
Acute arthritis models (reactive arthritis and gouty arthritis)
Intraperitoneal injection or oral gavage
60, 200, or 600 mg/kg
24 hours, 12 hours, and 1 hour before injection, and 11 hours and 23 hours after injection
Reduced joint swelling and inflammatory cell infiltration, decreased levels of IL-1β, IL-6, and CXCL1
Arthritis Res Ther. 2018 Aug 3;20(1):169
Mice
Mouse model of severe ischemic cardiomyopathy
Dietary administration
3.75 g/kg and 7.5 g/kg
Daily administration for 9 weeks
To evaluate the protective effects of OLT1177? on contractile reserve and diastolic function after myocardial infarction. Results showed that OLT1177? significantly preserved contractile reserve and diastolic function.
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