TABLE 2

Inhibitors of NLRP3 and mechanisms of inhibition

AgentTarget
(IC50)a
Mechanism of InhibitionDisease Model and Clinical TrialRefb
MCC950 (CRID3, CP-456773)NLRP3
(7.5 nM, BMDM)
(8.1 nM, HMDM)
Binding to NLRP3 NACHT.
Inhibition of ATP/ADP exchange and ATP hydrolysis.
Blocking of canonical, noncanonical, and alternative activation of NLRP3
Mouse models of EAE, CAPS, peritonitis, etc.
Phase II trial
1
CY-09NLRP3
(5 μM, BMDM)
Binding to Walker A motif of NLRP3 NACHT to inhibit ATPase and oligomerization.
Analog of CFTR(inh)-172 without inhibitory activity on CFTR
Mouse models of CAPS and type 2 diabetes.
Ex vivo gout patient monocytes
2
OridoninNLRP3
(0.5 μM, BMDM)
Covalent binding to NLRP3 NACHT Cys273 to block NLPR3-NEK7 interactionMouse models of peritonitis, gouty arthritis, and type 2 diabetes.
Anti-inflammation herbal medicine
3
C77Microglial
NLRP3
(4.1 μM)
NLRC4
(9.15 μM)
(Human THP-1)
Binding to NACHT of NLRP3 and NLRC4 to inhibit ATPase and IL-1β secretion in microglial cells.
Identified through in silica screening and in vitro and in vivo verification
Inhibit IL-1β production in brain regions of mice exposed to LPS, including frontal cortex, cortex, hippocampus, and cerebellum4
TranilastNLRP3
(25 μM, BMDM)
Binding to NLRP3 NACHT to block oligomerizationMouse models of Gouty arthritis, CAPS, and type 2 diabetes.
Anti-allergic drug
5
MNSNLRP3
(2 μM, BMDM)
Syk, Src
Binding to NLRP3 NACHT by targeting cysteine residues to inhibit ATPase and oligomerization.
Inhibition of Syk and Src kinases
Antiplatelet effect possibly by inhibition of tyrosine kinases6
Bay 11-7082NLRP3
(5 μM, BMDM)
NLRC4
IKK-β, E2/3, & PTP
Inhibition of NLRP3 NACHT ATPase, possibly by alkylating cysteine thiol.
Partial inhibition of NLRC4.
Inhibition of IKK-β, E2/3, and PTP
Broad anti-inflammatory activity7
OLT117NLRP3
(1 nM, mouse J774A.1 macrophages; 1 μM, HMDM)
Inhibition of NLRP3 NACHT ATPase and blocking of NLRP3 activationMouse LPS- induced systemic inflammation.
Phase II trial
8
BOT-4-oneNLRP3
(0.54-1.28 μM, BMDM)
NLRC4
Alkylating agent.
Inhibition of NLRP3 NACHT ATPase via alkylation.
Induction of ubiquitination of NLRP3.
Inhibition of IKK-β
Mouse MSU-induced peritonitis.
Immunomodulation of dermatitis and arthritis
9
INF39NLRP3
(10 μM, human THP-1)
Covalent biding to NLRP3 NACHT to inhibit ATPase and canonical and non-canonical activation of NLRP3Rat DNBS-induced colitis10
ParthenolideNLRP3
(5 μM, BMDM)
NLRP1, caspase 1, IKK-β
Alkylating agent.
Inhibition of NLRP3 NACHT ATPase, caspase 1, and IKK-β
Anti-inflammation herbal medicine11
Compound 17 (YQ128)NLRP3
(0.3 μM, mouse J774A.1 macrophages)
Second-generation benzenesulfonamide inhibitor of NLRP3.
Selective inhibition of NLRP3 in vitro and in vivo
Brain BBB penetrating
LPS induced activation of NLRP3 in peritoneal macrophages in mice.
Analog JC-124 ameliorates (a) amyloid pathology in mouse model of AD, (b) neuroinflammation in mouse TBI, and (c) infarct size in mouse AMI
12
  • aIC50, the concentration of a drug to result in 50% inhibition of a maximal activity. The IC50 for inhibition of induced production of IL1β in cultured macrophages and monocytes by common inducers, such as LPS, ATP, nigericin, and mineral particles, is often used to describe the potency of an inhibitor to inhibit the NLRP3 inflammasome. The types of cells used to determine IC50 are listed under each IC50 value.

  • bReference cited: 1. Coll et al., 2019; Coll et al., 2015; Perregaux et al., 2001; Tapia-Abellán et al., 2019; 2. Jiang et al., 2017; 3. He et al., 2018; 4. Sebastian-Valverde et al., 2021; 5. Huang et al., 2018; 6. He et al., 2014; 7. Jiang et al., 2017; Juliana et al., 2010; 8. Marchetti et al., 2018; 9. Shim et al., 2017; 10. Cocco et al., 2017; Pellegrini et al., 2018; 11. Jiang et al., 2017; Juliana et al., 2010; 12. Jiang et al., 2019.

  • AD, Alzheimer’s disease; AMI, acute myocardial infarction; BBB, blood-brain barrier; BMDM, mouse bone marrow-derived macrophage; CFTR, cystic fibrosis transmembrane conductance regulator; CRID, cytokine release inhibitory drug; DNBS, 2,4-dinitrobenznesulfonic acid; EAE, experimental autoimmune encephalomyelitis; HMDM, human monocyte-derived macrophage; IKK, IκB kinase; LPS, lipopolysaccharide; MNS, 3,4-methylenedioxy-beta-nitrostyrene; MSU, monosodium urate; NACHT, domain present in NAIP, CIITA, HET-E, and TP1; NEK7, never in mitosis gene A–related kinase 7; NLRC, nucleotide-binding domain (NB) and leucine-rich repeat (LRR) containing receptor (NLR) caspase-recruitment and activation domain (CARD)-containing; NLRP3, nucleotide-binding, oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3; PTP, protein tyrosine phosphatase; Src, Src kinase; Syk, spleen tyrosine kinase; TBI, traumatic brain injury; Trp, tryptophan.