Dreas, Agnieszka published the artcileDiscovery of indazole-pyridinone derivatives as a novel class of potent and selective MNK1/2 kinase inhibitors that protecting against endotoxin-induced septic shock, Quality Control of 939-99-1, the publication is European Journal of Medicinal Chemistry (2021), 113057, database is CAplus and MEDLINE.
The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clin. trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds I and II, selective and metabolically stable derivatives Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds I and II significantly improved survival rates of animals in the endotoxin LD challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.
European Journal of Medicinal Chemistry published new progress about 939-99-1. 939-99-1 belongs to chlorides-buliding-blocks, auxiliary class Fluoride,Chloride,Benzyl chloride,Benzene, name is 1-(Chloromethyl)-4-(trifluoromethyl)benzene, and the molecular formula is C8H6ClF3, Quality Control of 939-99-1.
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