INCA-6 - CAS 3519-82-2
Category: Inhibitor
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INCA-6, a cell-permeable quinone compound, is a selective and potent inhibitor of Calcineurin Nuclear Factor of Activated T cells (NFAT) signaling. It binds to calcineurin with high affinity and does not affect calcineurin activity or its downstream signaling. It blocks its dephosphorylation and nuclear import, thus interferes with downstream targets of NFAT including induction of cytokine mRNAs.
≥98% by HPLC
INCA-6; INCA 6; INCA6; 9,10-Dihydro-9,10-o-benzenoanthracene-1,4-dione; 9,10-Dihydro-9,10[1',2']-benzenoanthracene-1,4-dione; 1,4-Triptycenoquinone; 12,15-Dihydro-12,15-dioxotriptycene; NSC 25996; Triptycene-1,4-quinone
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1.NFAT isoforms play distinct roles in TNFα-induced retinal leukostasis.
Bretz CA;Savage SR;Capozzi ME;Suarez S;Penn JS Sci Rep. 2015 Nov 3;5:14963. doi: 10.1038/srep14963.
The objective of this study was to determine the role of individual NFAT isoforms in TNFα-induced retinal leukostasis. To this end, human retinal microvascular endothelial cells (HRMEC) transfected with siRNA targeting individual NFAT isoforms were treated with TNFα, and qRT-PCR was used to examine the contribution of each isoform to the TNFα-induced upregulation of leukocyte adhesion proteins. This showed that NFATc1 siRNA increased ICAM1 expression, NFATc2 siRNA reduced CX3CL1, VCAM1, SELE, and ICAM1 expression, NFATc3 siRNA increased CX3CL1 and SELE expression, and NFATc4 siRNA reduced SELE expression. Transfected HRMEC monolayers were also treated with TNFα and assayed using a parallel plate flow chamber, and both NFATc2 and NFATc4 knockdown reduced TNFα-induced cell adhesion. The effect of isoform-specific knockdown on TNFα-induced cytokine production was also measured using protein ELISAs and conditioned cell culture medium, and showed that NFATc4 siRNA reduced CXCL10, CXCL11, and MCP-1 protein levels. Lastly, the CN/NFAT-signaling inhibitor INCA-6 was shown to reduce TNFα-induced retinal leukostasis in vivo. Together, these studies show a clear role for NFAT-signaling in TNFα-induced retinal leukostasis, and identify NFATc2 and NFATc4 as potentially valuable therapeutic targets for treating retinopathies in which TNFα plays a pathogenic role.
2.P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways.
Shiratori M;Tozaki-Saitoh H;Yoshitake M;Tsuda M;Inoue K J Neurochem. 2010 Aug;114(3):810-9. doi: 10.1111/j.1471-4159.2010.06809.x. Epub 2010 May 13.
Microglia plays an important role in many neurodegenerative conditions. ATP leaked or released by damaged cells triggers microglial activation through P2 receptors, and stimulates the release of oxygen radicals, proinflammatory cytokines and chemokines from activated microglia. However, little is known about mechanisms underlying ATP-induced chemokine release from microglia. In this study, we found that a high concentration of ATP induces the mRNA expression and release of CXCL2 from microglia. A similar effect was observed following treatment of microglia with a P2X7 receptor (P2X7R) agonist, 2'-and 3'-O-(4-benzoylbenzoyl) ATP, and this was inhibited by pre-treatment with a P2X7R antagonist, Brilliant Blue G. ATP induced both activation of nuclear factor of activated T cells (NFAT) and MAPKs (p38, ERK, and JNK) through P2X7R. ATP-induced mRNA expression of CXCL2 was inhibited by INCA-6 (an NFAT inhibitor), SB203580 (a p38 inhibitor), U0126 (a MEK-ERK inhibitor) and JNK inhibitor II (a JNK inhibitor). However, MAPK inhibitors did not inhibit activation of NFAT. In addition, protein kinase C inhibitors suppressed ATP-induced ERK and JNK activation, and also inhibited ATP-induced CXCL2 expression in microglia.
3.Calcineurin inhibitors regulate fibroblast growth factor 23 (FGF23) synthesis.
Bär L;Großmann C;Gekle M;Föller M Naunyn Schmiedebergs Arch Pharmacol. 2017 Nov;390(11):1117-1123. doi: 10.1007/s00210-017-1411-2. Epub 2017 Jul 31.
Fibroblast growth factor 23 (FGF23) inhibits renal phosphate reabsorption and calcitriol formation, effects depending on Klotho as a co-receptor for FGF23. In addition, FGF23/Klotho strongly influences aging and the onset of age-associated diseases. The synthesis of FGF23 by bone cells is induced by store-operated Ca;2+; entry (SOCE) through Orai1 in UMR106 osteoblast-like cells. Ca;2+; entry activates the phosphatase calcineurin in many cell types which dephosphorylates nuclear factor of activated T cells (NFAT) thereby stimulating its transcriptional activity. Here, we explored whether calcineurin-NFAT signaling impacts on FGF23 production. Fgf23 transcripts were determined by qRT-PCR and FGF23 protein by ELISA. Calcineurin as well as NFAT expression were quantified by RT-PCR in UMR106 cells. UMR106 cells expressed calcineurin subunits Ppp3r1, Ppp3ca, Ppp3cb, and Ppp3cc as well as NFATc1, NFATc3, and NFATc4. Calcineurin inhibitors ciclosporin A (CsA) and tacrolimus (FK-506) decreased Fgf23 gene expression and FGF23 protein production. Moreover, calcineurin-NFAT interaction inhibitor INCA-6 reduced the abundance of Fgf23 transcripts as well as FGF23 protein. Calcineurin-NFAT signaling is a potent regulator of FGF23 formation.
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CAS 3519-82-2 INCA-6

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