A Probe for NLRP3 Inflammasome Inhibitor MCC950 Identifies Carbonic Anhydrase 2 as a Novel Target.
ACS Chem Biol
; 16(6): 982-990, 2021 06 18.
Article
em En
| MEDLINE
| ID: mdl-34003636
ABSTRACT
Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Anidrase Carbônica II
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Inflamassomos
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Proteína 3 que Contém Domínio de Pirina da Família NLR
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Furanos
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Indenos
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Macrófagos
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article