Targeting pyroptosis in inflammatory bowel disease: A potentially effective therapeutic approach

Table 1 Small-molecule inhibitors and repurposed drugs of pyroptosis-related proteins

Name	Target protein	Pharmacological mechanism	IBD disease model	Clinical stage	Ref.
MCC950 (CP-456773)	NLRP3	Binds to the NACHT domain of NLRP3, preventing ATP hydrolysis and oligomerization	Winnie spontaneous colitis, DSS-induced acute colitis	Phase II discontinued (rheumatoid arthritis)	Perera et al[15]; Wang et al[31]; Coll et al[49]; Saber et al[50]; Saber and El-Kader[51]; Li et al[52]; Liu et al[53]
OLT1177 (dapansutrile)	NLRP3	Binds NLRP3 LRR domain, blocks NLRP3 inflammasome assembly	DSS-induced acute colitis	Phase II completed (osteoarthritis; No. NCT02104050); phase III planned (gout; No. NCT05658575)	Oizumi et al[35]; Marchetti et al[54]; Saber et al[55]
INF39	NLRP3	Irreversibly inhibits NLRP3 ATP activity	DNBS-induced colitis	Preclinical	Shi et al[56]; Pellegrini et al[57]
VI-16	TXNIP-NLRP3	Disrupts TXNIP-NLRP3 interaction, reduces oxidative stress	DSS-induced colitis, LPS-stimulated THP-1/BMDM	Preclinical	Zhao et al[58]
CY-09	NLRP3	Binds NLRP3 NACHT domain to block ATP activity	LPS-stimulated BMDM	Preclinical	Jiang et al[59]
VX-740 (pralnacasan)	Caspase-1	Reversible competitive caspase-1 inhibitor	DSS-induced acute colitis	Phase II discontinued (rheumatoid arthritis)	Bauer et al[60]; Dhani et al[61]
VX-765 (belnacasa)	Caspase-1	Prodrug of VRT-043198, a reversible caspase-1 inhibitor	DSS-induced acute colitis	Phase II discontinued (epilepsy; No. NCT01501383)	Wang et al[36]; Dhani et al[61]
Ac-YVAD-CMK	Caspase-1	Irreversible covalent inhibitor (chloromethylketone modification of Cys285)	DNBS-induced colitis	Preclinical	Pellegrini et al[57]
Necrosulfonamide	GSDMD	Alkylates GSDMD to prevent pore formation	DSS-induced acute colitis	Preclinical	Rathkey et al[62]; Yang et al[63]
Metformin	AMPK/NLRP3	AMPK activation inhibits NLRP3 inflammasome assembly	DSS-induced acute colitis	Marketed (T2DM); IBD trials ongoing (No. NCT05574387)	Hosseini et al[64]; Cao et al[65]; El-Haggar et al[66]
Tranilast	NLRP3	Inhibits NLRP3 oligomerization and ASC speck formation	DSS/TNBS-induced colitis	Marketed (anti-allergic)	Huang et al[67]; Seto et al[68]; Oshitani et al[69]
Disulfiram	GSDMD	Covalent modification of GSDMD to inhibit pore formation	DSS/TNBS-induced colitis	Marketed (alcohol addiction)	Chi et al[70]; Lei et al[71]; Zhou et al[72]; Ou et al[73]; Luo et al[74]
Dimethyl fumarate	GSDMD	Covalent modification of GSDMD to inhibit pore formation	DSS-induced colitis	Marketed (multiple sclerosis)	Humphries et al[75]; Li et al[76]; Patel et al[77]; Buscarinu et al[78]; Shah et al[79]

Detailed information regarding primary endpoints and adverse reactions for these candidate drugs is selectively summarized in the corresponding drug profiles within the “small-molecule inhibitors: Precision targeting of key pyroptotic nodes” subsection of the main text. NLRP3: Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3; GSDMD: Gasdermin D; AMPK: Adenosine 5’-monophosphate-activated protein kinase; ATP: Adenosine triphosphate; LRR: Leucine-rich repeat; ASC: Adapter protein apoptosis-associated speck-like protein containing a CARD; DSS: Dextran sulfate sodium; DNBS: Dinitrobenzene sulfonic acid; TNBS: 2,4,6-trinitrobenzenesulfonic acid solution; T2DM: Type 2 diabetes mellitus; IBD: Inflammatory bowel disease.

Table 2 Biologics of pyroptosis-related proteins

Name	Target protein	Pharmacological mechanism	Pyroptotic diseases	Clinical stage	Ref.
Canakinumab (ilaris)	IL-1β	IL-1β monoclonal antibody, inhibits NLRP3 downstream effects	Cryopyrin-associated periodic syndromes	Phase III completed (SJIA; No. NCT02396212)	Shaul et al[81]; Miyamoto et al[82]
Anakinra	IL-1	Recombinant IL-1 receptor antagonist	Rheumatoid arthritis; Winnie-TNF-KO murine model (IBD)	Phase IV (RA; No. NCT00121043)	Liso et al[83]; Dogan et al[84]; Truyens et al[85]
GSK1070806	IL-18	Humanized monoclonal antibody against IL-18	Rheumatoid arthritis; Crohn’s disease	Phase II (CD; No. NCT03681067)	Guha et al[86]
DFV890	NLRP3	Oral NLRP3 inhibitor (small molecule biologic)	Coronary heart disease; COVID-19	Phase II (COVID-19; No. NCT04382053)	Shen et al[87]; Gatlik et al[88]; Madurka et al[89]
NLRP3-ASO	NLRP3 mRNA	Antisense oligonucleotide suppressing NLRP3	Cryopyrin-associated periodic syndromes; Alzheimer’s disease	Preclinical	Kaufmann et al[90]; Braatz et al[91]
IC100 (ASC-mAb)	ASC speck	Monoclonal antibody blocking inflammasome assembly	Retinopathy of prematurity; Parkinson’s disease	Preclinical	de Rivero Vaccari et al[92]; Yuan et al[93]; Cyr et al[94]
Caspase-1 siRNA	Caspase-1 mRNA	siRNA silencing caspase-1 expression	Alzheimer’s disease	Preclinical	Han et al[95]
GSDMD-Nb	GSDMD	Nanobody binding GSDMD-N terminus to prevent pore formation	Sepsis	Preclinical	Schiffelers et al[96]

Detailed information regarding primary endpoints and adverse reactions for these biologics is selectively summarized in the corresponding agent profiles within the “biologics: Next-generation targeted intervention approaches” subsection of the main text.

NLRP3: Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3; ASC: Adapter protein apoptosis-associated speck-like protein containing a CARD; IL: Interleukin; ASO: Antisense oligonucleotide; siRNA: Small interfering RNA; GSDMD: Gasdermin D; mRNA: Messenger RNA; TNF: Tumor necrosis factor; KO: Knockout; IBD: Inflammatory bowel disease; COVID-19: Coronavirus disease 2019; SJIA: Systemic juvenile idiopathic arthritis; CD: Crohn’s disease; RA: Rheumatoid arthritis.