MCC950 sodium (Synonyms: CRID3 sodium salt )

MCC950 is a potent, selective, small molecule inhibitor of NLRP3. MCC950 blocks canonical and non-canonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibits NLRP3 but not AIM2, NLRC4 or NLRP1 activation. MCC950 reduces Interleukin-1p (IL-1β) production in vivo and attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescues neonatal lethality in a mouse model of CAPS and is active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for the further study of the NLRP3 inflammasome in human health and disease.^[1]

The half-maximal inhibitory concentration (IC₅₀) of MCC950 in BMDM was approximately 7.5 nM, while in HMDM it had a similar inhibitory capacity (IC₅₀ = 8.1 nM). Cells were first primed with LPS then pre-treated with MCC950 and lastly stimulated with the NLRP3 stimulus ATP. Treating cells with nanomolar concentrations of MCC950 dose dependently inhibited the release of IL-1β in BMDM, HMDM and PBMC. ^[1]

Mice were pre-treated with MCC950 one hour before i.p. injection of LPS and were assessed two hours later. Pre-treatment with MCC950 reduced serum concentrations of IL-1β and IL-6 while it did not considerably decrease the amount of TNF-α, indicating that MCC950 is active in vivo.Besides, treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1βexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice.^[1,2]

References:
[1]. Coll, Rebecca C et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature medicine vol. 21,3 (2015): 248-55.
[2]. Zhai, Yadong et al. Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. Molecules (Basel, Switzerland) vol. 23,3 522. 27 Feb. 2018.