Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets

Abstract

This version of the article has been accepted for publication, after peer review but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections.

Novel chemotype NLRP3 inhibitors that target the CRID3-binding pocket with high potency

“…However, chronic IL-1-blockade increases risk for fatal infections and sepsis, suggesting that upstream targeting of the NLRP3 inflammasome may potentially be a safer and more efficacious therapeutic strategy as it would block production of the central inflammatory mechanisms that contribute to the pathology while at the same time keeping non-targeted inflammasomes available to produce IL-1β to cope with infections ( Ridker et al, 2017 ). Hence, there is substantial interest in developing selective and potent NLRP3-targeted inhibitors for the treatment of CAPS and other diseases ( Vande Walle & Lamkanfi, 2024 ).…”

“…The clinical manifestations of CAPS exhibit a spectrum of severity, with familial cold autoinflammatory syndrome representing the mildest form, Muckle–Wells syndrome (MWS) demonstrating moderate severity, and neonatal-onset multisystem inflammatory disease/chronic infantile neurological, cutaneous and articular syndrome manifesting as the most severe subtype of CAPS ( Van Opdenbosch & Lamkanfi, 2019 ). Because of its extensive involvement across disease indications, selective and potent inhibitors of the NLRP3 inflammasome have considerable therapeutic potential ( Vande Walle & Lamkanfi, 2024 ). Early studies with sulfonylurea compounds served as proof of concept for achieving selective inhibition of the NLRP3 inflammasome using small molecules ( Lamkanfi et al, 2009 ; Coll et al, 2015 ).…”

“…Early studies with sulfonylurea compounds served as proof of concept for achieving selective inhibition of the NLRP3 inflammasome using small molecules ( Lamkanfi et al, 2009 ; Coll et al, 2015 ). Among these, CRID3 (also named MCC950) stands out as an inhibitor that exhibits selective NLRP3 inhibition with nM potency, and it is widely used in preclinical studies ( Mangan et al, 2018 ; Vande Walle & Lamkanfi, 2024 ). In addition, structural biology studies, utilizing both X-ray crystallography and cryo-electron microscopy, have recently elucidated the binding pocket of CRID3 at a cleft situated at the interface of the four subdomains constituting the central NACHT region of NLRP3 ( Dekker et al, 2021 ; Hochheiser et al, 2022 ; McBride et al, 2022 ).…”

“…This structural insight provides valuable knowledge regarding the mechanistic basis of NLRP3 inhibition by CRID3, revealing that CRID3 binding in this pocket maintains NLRP3 in an inactive conformation by preventing ADP/ATP exchange ( Dekker et al, 2021 ; Hochheiser et al, 2022 ; McBride et al, 2022 ). Capitalizing on these scientific breakthroughs, several therapeutic NLRP3 inhibitors based on the CRID3 scaffold are under development, with the most advanced candidates currently undergoing phase 2 clinical trials in humans ( Vande Walle & Lamkanfi, 2024 ).…”

Cell death‑related molecules and targets in the progression of urolithiasis (Review)

“…Whereas caspase-3/7 are involved in apoptosis, inflammatory caspase-1/4/5/11 mediate pyroptosis by cracking GSDMD ( 40 ). Various pathogenic microorganisms and endogenous harmful substances can activate the NLRP3 inflammasome, which can assemble the intracytoplasmic innate immune complex, activate the cysteine protease caspase-1, and then lyse GSDMD, eventually leading to pyroptosis ( 70 , 71 ). As a sensor required for inflammasome formation, NLRP3 plays a key role in oxalate-associated renal failure ( 72 ).…”