The title of the article is: "Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues, including inflammasome priming signals".
ATI-450, an investigational drug formerly known as CDD-450, is a unique p38α MAPK–MK2 pathway selective inhibitor used to uncover the function of this protein complex in inflammasome priming signals. Importantly, ATI-450 is as efficacious as global p38α MAPK inhibitors in decreasing inflammation in disease models. Cryopyrin-Associated Periodic Syndrome (CAPS) and the most severe form of the disease, Neonatal-Onset Multisystem Inflammatory Disease (NOMID) result from dysregulated inflammasome generating elevated systemic levels of the cytokine IL-1β. As the article elucidates:
- Selective inhibition of p38α MAPK –MK2 decreases IL-1β, IL-6, and TNF-α production by promoting mRNA instability.
- ATI-450 attenuates NOMID-associated complications in a transgenic mouse model of CAPS.
- ATI-450 prevents bone destruction in CAPS mice.
- ATI-450 inhibits IL-1β in blood cells from CAPS patients
- ATI-450 prevents inflammation and joint destruction in inflammatory arthritis in rats.
ATI-450 selectively blocks p38α MAPK activation of the proinflammatory kinase MK2 while sparing p38α activation of other effectors such as PRAK and ATF2. Use of ATI-450 helped to reveal a critical role of the p38α MAPK –MK2 pathway in NLRP3 inflammasome priming. ATI-450 also inhibited other inflammatory pathways (e.g., TNF-α and IL-6), thus implying potential indications for this drug candidate beyond inflammasopathies. These findings may have potential clinical implications because ATI-450 is at least as efficacious as clinically evaluated global p38α MAPK inhibitors in suppressing inflammation in both animal disease models and patients’ cells, and ATI-450’s offers the potential lack of transient efficacy and safety issues associated with global p38α MAPK inhibitors which may result from their inhibition of non-MK2 substrates involved in anti-inflammatory and housekeeping functions.
This study was carried out by
The article is available at http://jem.rupress.org/cgi/doi/10.1084/jem.20172063 and will appear in print form on
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