NOD-like Receptor (NLR) Inhibitor

(+)-Magnoflorine (α-Magnoflorine) chloride is an orally active aporphine alkaloid with multiple biological activities. (+)-Magnoflorine chloride promotes Parkin/PINK1-mediated mitochondrial autophagy, inhibits the activation of NLRP3/Caspase-1 pathway, regulates the intestinal microbiota, and exhibits significant anti-inflammatory and immunomodulatory activities. (+)-Magnoflorine chloride inhibits JNK and TLR4/NF-κB signaling pathways, activates Sirt1/AMPK pathway, alleviates neuronal oxidative stress and apoptosis. Magnoflorine chloride upregulates miR-410-3p, inhibits HMGB1/NF-κB pathway, and has anti-tumor activity. (+)-Magnoflorine chloride also has significant antifungal activity.

Ruvonoflast (NT-0796) is an orally active, selective and CNS-penetrant NLRP3 inflammasome inhibitor. Ruvonoflast inhibits IL-1β release in human PBMC cells with an IC₅₀ value of 0.32 nM. Ruvonoflast is an isopropyl ester that undergoes intracellular conversion to Ruvonoflast, the carboxylic acid active species. Ruvonoflast reverses high fat diet-induced obesity, systemic inflammation and astrogliosis in the diet-induced obesity mouse model. Ruvonoflast is promising for research of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.

Alirocumab (anti-PCSK9) is an anti-PCSK9 human monoclonal antibody. Alirocumab (anti-PCSK9) inhibits PCSK9. Alirocumab (anti-PCSK9) reduces NLRP3 inflammasome, regulates Nrf2/HO-1, HMGB1/NF-κB and Fractalkine/CX3CR1. Alirocumab (anti-PCSK9) increases the ability of the liver to bind LDL-cholesterol (LDL-C) and reduces levels of LDL-C in blood. Alirocumab (anti-PCSK9) improves atherosclerosis and inflammation.

Ofirnoflastum (Ofirnoflast) is an orally active first-in-class allosteric NEK7 inhibitor with an IC₅₀ of 46 nM. Ofirnoflastum binds an allosteric site adjacent to NEK7’s ATP-binding pocket, induces conformational shifts, disrupts NEK7-NLRP3 binding, blocks NLRP3 inflammasome assembly, spares NEK7’s physiological functions, and suppresses caspase-1, caspase-8, NF-κB, and TNF activity. Ofirnoflastum reduces pro-inflammatory cytokine production, suppresses ASC specks, IL-1β release, pyroptotic cell death, and leukemic burden, induces apoptosis and erythroid differentiation, restores hematopoiesis, and improves outcomes in colitis models. Ofirnoflastum can be used for the research of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.

AZD4144 is an orally active NLRP3 inhibitor (EC₅₀: 0.082 μM). AZD4144 effectively inhibits the release of IL-1β when NLRP3 is overactivated, exerting an anti-inflammatory effect. AZD4144 has low inhibitory effect on hERG and low cardiotoxicity. AZD4144 has the potential to study diseases and conditions associated with NLRP3 inflammasome activation.

Plantainoside D, a phenylethanoid glycosides, is a IKK-β inhibitor with diverse biological activities. Plantainoside D shows inhibitory activity of angiotensin-converting enzyme (ACE) with an IC₅₀ of 2.17 mM. Plantainoside D significantly reduces the release of glutamate from nerve terminals in the cerebral cortex of rats by inhibiting the voltage-dependent calcium channel (VDCCs) and protein kinase C (PKC) signaling cascade. Plantainoside D significantly alleviates cell apoptosis by inhibiting the generation of ROS and the activation of NF-κB. Plantainoside D significantly improves acute lung injury (ALI) induced by sepsis by regulating the Sirt3/NLRP3 signaling pathway. Plantainoside D can be used for the study of neuroprotection, antioxidant, anti-inflammation, antihypertension.

NP3-253 is an orally active and brain-penetranted NLRP3 inflammasome inhibitor. NP3-253 functions as a molecular glue that prevents NACHT-subdomain rearrangements, locking NLRP3 in an inactive conformation. NP3-253 inhibits production of pro-inflammatory cytokines IL-1β and IL-18. NP3-253 can be used for the research of inflammation and neurological disease, suah as peritonitis.

NK7-902 diTFA is a selective and orally active CRBN-dependent NEK7 molecular glue degrader with K_d values of 1.5 and 2.6 μM for hNEK7 and mNEK7. NK7-902 diTFA fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3-dependent IL-1β production. NK7-902 diTFA shows activity in murine systems and induces a profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation. NK7-902 diTFA can be used for the research of inflammation, such as cryopyrin-associated periodic syndromes.

Thiolutin (Acetopyrrothin) is a sulfur-containing antibiotic, which is a potent inhibitor of bacterial and yeast RNA polymerases. Thiolutin can be produced by Streptomyces. Thiolutin inhibits AMSH (IC₅₀ = 4 μM) and Rpn11 (IC₅₀ = 0.53 μM). Thiolutin is a dual inhibitor of BRCC36 and the NLRP3 inflammasome, exhibiting anti-inflammatory effects. Thiolutin effectively suppresses the interaction between BRCC36 and HMGCR, leading to the inhibition of HCC growth. Thiolutin attenuates pyroptosis and NLRP3 inflammasome activation. Thiolutin markedly alleviates renal injury and inflammatory process in IgAN. Thiolutin is an anti-angiogenic compound which can ease Doxorubicin-induced cardiotoxicity (DOXIC)^{[1][2][3][4][5]}.

Tomaralimab (OPN-305) is a humanized anti-TLR2 IgG4 monoclonal antibody. Tomaralimab inhibits TLR2, MyD88, NLRP3, and reduces pro-inflammatory cytokine (IL-1β, IL-6, IL-8) production. Tomaralimab reduces tau pathology. Tomaralimab improves cognition, atopic dermatitis. Tomaralimab has anticancer effects on pancreatic ductal adenocarcinoma. Tomaralimab is being studied in myelodysplastic syndrome (MDS), atopic dermatitis, pancreatic ductal adenocarcinoma, Alzheimer's disease, and myocardial ischemia/reperfusion injury.

Dexpramipexole ((R)-Pramipexole) dihydrochloride is an orally active, blood-brain barrier permeable mitochondrial protective agent. Dexpramipexole dihydrochloride upregulates the expression of Parkin, PINK1, GPX4 and FSP1; binds to mitochondrial F1/Fo-ATP synthase; blocks the Na_v1.8 sodium channel; and inhibits the activation of the NLRP3 inflammasome. Dexpramipexole dihydrochloride induces mitophagy, inhibits ferroptosis, pyroptosis, apoptosis, neuroinflammation and eosinophilopoiesis; maintains mitochondrial function and redox homeostasis; reduces reactive oxygen species production; and decreases myocardial infarct size. Dexpramipexole dihydrochloride is applicable to studies on eosinophilic asthma, myocardial ischemia/reperfusion injury, sepsis-associated encephalopathy, analgesia, and more.

(±)11(12)-EET is a NLRP3 inflammasome inhibitor. (±)11(12)-EET can be used for the research of anti-inflammatory, angiogenic and cardioprotective.

BAL-0028 is a reversible inhibitor of NLRP3 activation with an IC₅₀ value of 25 nM. BAL-0028 binds closely to the NACHT domain of the NLRP3 with K_D values of 104-123 nM. BAL-0028 can inhibit the secretion of IL-1β and has anti-inflammatory activity.

NOD-IN-1 is a potent mixed inhibitor of nucleotide-binding oligomerization domain (NOD)-like receptors, NOD1 and NOD2, with IC₅₀ of 5.74 μM and 6.45 μM, respectively.

(S)-(+)-Carvone is an orally active natural product. (S)-(+)-Carvone increases the activity of antioxidant enzymes (SOD, CAT) and ROS, reduces the levels of oxidative stress markers (MDA, AChE), reduces the secretion of proinflammatory cytokines (IL-1β, IL-4, IL-6, IL-10), and downregulates NLRP3. (S)-(+)-Carvone increases the activities of caspase-8, -9 and -3. (S)-(+)-Carvone induces apoptotic death. (S)-(+)-Carvone has antimanic-like effect, liver protection and anticancer activity against skin cancer. (S)-(+)-Carvone improves memory and arthritis.

Epimedin A, one of the main flavonoid active components in Herba Epimedii, is orally active. Epimedin A can inhibit osteoclastogenesis, differentiation, and bone resorption. Epimedin A also possesses anti-inflammatory activity. Epimedin A can be used in the research of osteoporosis and inflammatory diseases.

Dehydrodiisoeugenol is an orally active anti-inflammatory and anti-tumor agent. Dehydrodiisoeugenol inhibits the proliferation of colorectal cancer cells, and induces apoptosis, autophagy, endoplasmic reticulum stress and cell cycle arrest. Dehydrodiisoeugenol also exerts anti-inflammatory effects by inhibiting the activation of NF-κB and the expression of COX-2. Dehydrodiisoeugenol can be used in the research related to colorectal cancer, inflammatory diseases and ulcerative colitis.

CVN293 is a selective and brain permeable potassium ion (K⁺) channel KCNK13 inhibtor with IC₅₀s of 41 nM and 28 nM for hKCNK13 and mKCNK13, respectively. CVN293 potently inhibits the NLRP3-inflammasome mediated production of the proinflammatory cytokine IL-1β in microglia.

Arglabin ((+)-Arglabin), a natural product isolated from Artemisia glabella, is a NLRP3 inflammasome inhibitor. Arglabin shows anti-inflammatory and antitumor activities. The antitumor activity of Arglabin proceeds through its inhibition of farnesyl transferase which leads to the activation of RAS proto-oncogene.

(+)-Magnoflorine (α-Magnoflorine) iodide is an orally active aporphine alkaloid with multiple biological activities. (+)-Magnoflorine iodide promotes Parkin/PINK1 -mediated mitochondrial autophagy, inhibits the activation of NLRP3/Caspase-1 pathway, regulates the intestinal microbiota, and exhibits significant anti-inflammatory and immunomodulatory activities. (+)-Magnoflorine iodide inhibits JNK and TLR4/NF-κB signaling pathways, activates Sirt1/AMPK pathway, alleviates neuronal oxidative stress and apoptosis. Magnoflorine upregulates miR-410-3p, inhibits HMGB1/NF-κB pathway, and has anti-tumor activity. (+)-Magnoflorine iodide also has significant antifungal activity.