Synonyms: ATI-450 | ATI450 | CDD-450 | CDD450
Compound class:
Synthetic organic
Comment: We obtained the chemical structure for zunsemetinib from WHO Proposed list 125 of July 2021. This mapped to PubChem CID 86291496. The compound is claimed in Confluence Life Sciences' patent US9115089B2 as kinase inhibitor with potential to treat p38 kinase-mediated diseases [2]. Confluence Life Sciences is a subsidiary of Aclaris Therapeutics. We speculate that zunsemetinib is the MAPK-activated protein kinase 2 (MK2) inhibitor ATI-450 (formerly CDD-450 [3]), that is included on Aclaris' pipeline page. Phase 1 safety and tolerability of ATI-450 were reported in June 2021 [1]. This article described ATI-450 as an inhibitor of p38α/MK2 pathway-mediated inflammatory signalling, but discloses only a partial chemical structure in a supplementary figure. The same incomplete chemical structure appears in [3]. ATI-450 binds with high affinity to the interface of the p38MAPK-MK2 complex and selectively inhibits p38MAPK-catalysed phosphorylation of MK2 which stabilises the inactive conformation of MK2, and subsequently reduces inflammatory cytokine levels [3].
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References |
1. Gordon D, Hellriegel ET, Hope HR, Burt D, Monahan JB. (2021)
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study. Clin Pharmacol, 13: 123-134. [PMID:34140814] |
2. Hockerman SL, Monahan JB, SelnessSR. (2015)
Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds. Patent number: US9115089B2. Assignee: Confluence Life Sciences Inc. Priority date: 07/06/2013. Publication date: 25/08/2015. |
3. Wang C, Hockerman S, Jacobsen EJ, Alippe Y, Selness SR, Hope HR, Hirsch JL, Mnich SJ, Saabye MJ, Hood WF et al.. (2018)
Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. J Exp Med, 215 (5): 1315-1325. [PMID:29549113] |