Krakow, Poland – December 3, 2020 – Researchers from Ryvu Therapeutics, in collaboration with scientists from the Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, have jointly published a research paper presenting the possible relevance of MNKs inhibitors as a potential for the treatment of inflammatory diseases, including sepsis.
The article “Discovery of indazole-pyridinone derivatives as a novel class of potent and selective MNK1/2 kinase inhibitors that are protecting against endotoxin-induced septic shock” was published on December 1, 2020, in the „European Journal of Medicinal Chemistry”.
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 the first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as a treatment strategy for inflammatory conditions. Researchers present results of the optimization of indazole-pyridinone derived MNK1/2 inhibitors, among which are compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice, compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose 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.
Access to the article: https://www.sciencedirect.com/science/article/abs/pii/S0223523420310291