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PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene. The principal enzymatic activity of PIKfyve is to phosphorylate PtdIns3P to PtdIns(3,5)P2. PIKfyve activity is responsible for the production of both PtdIns(3,5)P2 and phosphatidylinositol 5-phosphate (PtdIns5P). PIKfyve is a large protein, containing a number of functional domains and expressed in several spliced forms. By directly binding membrane PtdIns(3)P, the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes. Impaired PIKfyve enzymatic activity by dominant-interfering mutants, siRNA- mediated ablation or pharmacological inhibition causes endosome enlargement and cytoplasmic vacuolation due to impaired PtdIns(3,5)P2 synthesis. Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several aspects of endosome dynamics, thereby affecting a number of trafficking pathways that emanate from or traverse the endosomal system en route to the trans-Golgi network or later compartments along the endocytic pathway.

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A potent IL-12/IL-23 inhibitor that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines (IC50=2 nM); suppresses Th1 but not Th2 immune response in mice; binds to PIKfyve and blocks its phosphotransferase activity (IC50=14 nM), has no activity on PIP4K, PIP5K, mTOR, PI3K and PI4K isoforms; also potently blocks infections by EBOV and MARV in Huh 7, Vero E6 and primary human macrophage cells with IC50 of 10 nM.




YM-201636 is a potent, selective PIKfyve inhibitor with IC50 of 33 nM, does not inhibits type Iiγ/Iα PtdInsP kinases even at 10 uM (p110α IC50=3.3 uM); shows insensitivity against yeast orthologue of PIKfyve, Fab1; significantly decreases the production of PtdIns(3,5)P2 by 80% in serum-starved NIH3T3 cells with no effect on serum-stimulated PKB Ser 473 phosphorylation at 0.8 uM; inhibits basal and insulin-activated 2-deoxyglucose uptake withIC50 of 54 nM; significantly reduces retroviruses budding from cells; blocks the continuous recycling of the tight junction proteins claudin-1 and claudin-2 in MDCK cells.

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