Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

Cocco, Mattia; Pellegrini, Carolina; Martínez-Banaclocha, Helios; Giorgis, Marta; Marini, Elisabetta; Costale, Annalisa; Miglio, Gianluca; Fornai, Matteo; Antonioli, Luca; López-Castejón, Gloria; Tapia-Abellán, Ana; Angosto-Bazarra, Diego; Hafner-Bratkovič, Iva; Regazzoni, Luca; Blandizzi, Corrado; Pelegrı́n, Pablo; Bertinaria, Massimo

doi:10.1021/acs.jmedchem.6b01624

Cited by 137 publications

(113 citation statements)

References 52 publications

(149 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…A series of acrylate derivative compounds, IFN58 (IC 50 of 74 μM), IFN39 (IC 50 of 10 μM), and BOT‐4‐one (3 μM), a benzoxathiole derivative, inhibit ATPase activity of the NLRP3 inflammasome . BOT‐4‐one (3 μM) modulates ATPase activity of the NLRP3 inflammasome through enhancement of the ubiquitination level of NLRP3 …”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

“…123 A series of acrylate derivative compounds, IFN58 (IC 50 of 74 μM), IFN39 (IC 50 of 10 μM), and BOT-4-one (3 μM), a benzoxathiole derivative, inhibit ATPase activity of the NLRP3 inflammasome. [124][125][126] BOT-4-one (3 μM) modulates ATPase activity of the NLRP3 inflammasome through enhancement of the ubiquitination level of NLRP3. [127][128][129] In addition, many promising compounds, such as 2-aminoethaxydiphenyl borate (2-APB), which belongs to a novel boron compound series, and Fc11a-2 and OLT1177, have been reported to inhibit the NLRP3 inflammasome and the release of proinflammatory cytokines.…”

Section: Small-molecule Inhibitors Of the Nlrp3 Inflammasomementioning

confidence: 99%

See 1 more Smart Citation

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

View full text Add to dashboard Cite

Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

show abstract

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

Section: Small-molecule Inhibitors Of the Nlrp3 Inflammasomementioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The possibility of sulforaphane's inhibition of AIM2 or NLRC4 inflammasomes compromising their role in host defense was indicated before 42 . The extensive anti-inflammatory activity of various drugs including BAY 11-7082, INF39, sulforaphane, β-hydroxybutyrate, isoliquiritigenin and parthenolide [43][44][45][46][47][48] indicates their potential side effects as immunosuppressive agents, which may enhance the possibility of infection. Inhibition of NLRP3 inflammasome activation could be achieved by different compounds by various mechanisms, and these include the flufenamic acid and mefenamic acid effects on chloride efflux, influence on potassium ion efflux by BHB, and the effects of MCC950 on chloride and other volume-regulated anion channels.…”

Section: Discussionmentioning

confidence: 99%

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis

Kim

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC 50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA. Rheumatoid arthritis (RA) presents with characteristic chronic synovial hyperplasia and inflammation, and is a type of systemic autoimmune disease. Besides, in RA is also associated with invasion of inflammation and hyperplasia into the adjacent bone and cartilage, which cause slow degeneration of the knee joints 1. The current drugs for treating RA, such as disease-modifying anti-rheumatic drugs (methotrexate), nonsteroidal anti-inflammatory drugs (NSAID), steroids (prednisone), glucocorticoids, immunosuppressants, and biological therapies (TNF-α and IL-1 activity blocking monoclonal antibodies), have dramatically improved prognosis 2,3. Nevertheless, about 20-40% proportion of patients fail to respond to current therapies, and biological therapies raises the risk of serious infection 1,4,5. Therefore, attention has urgently focused on alternative RA therapeutics with high efficacy and reduced side effects.

show abstract

“…The success of INF4E and associated covalent warhead compounds in inhibiting caspase-1 processing led to the development of structurally related inhibitors. One compound, INF39 (2,4-dinitrobenzenesulfonic acid), identified by Cocco and colleagues in 2017, displayed strong anti-pyroptotic properties and an IC 50 value of 10 nM [ 213 ]. This irreversible inhibitor could decrease IL-1β release in BMDMs with low cytotoxicity.…”

Section: Pharmacological Inhibitors Of Nlrp3 Atpase Activitymentioning

confidence: 99%

ATP-Binding and Hydrolysis in Inflammasome Activation

2020

View full text Add to dashboard Cite

The prototypical model for NOD-like receptor (NLR) inflammasome assembly includesnucleotide-dependent activation of the NLR downstream of pathogen- or danger-associatedmolecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomericplatforms that lie upstream of inflammatory responses associated with innate immunity. Asmembers of the STAND ATPases, the NLRs are generally thought to share a similar model of ATPdependentactivation and effect. However, recent observations have challenged this paradigm toreveal novel and complex biochemical processes to discern NLRs from other STAND proteins. Inthis review, we highlight past findings that identify the regulatory importance of conserved ATPbindingand hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explorerecent breakthroughs that generate connections between NLR protein structure and function.Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectiveson the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations ofNLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctionsin nucleotide-binding domain topology with occupancy of ATP or ADP that are in turndisseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATPbindingand hydrolysis properties of NACHT domains in different NLRs integrate with signalingmodules and binding partners to control innate immune responses at the molecular level.

show abstract

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

Cited by 137 publications

References 52 publications

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis

ATP-Binding and Hydrolysis in Inflammasome Activation

Contact Info

Product

Resources

About