GO-6976 - CAS 136194-77-9
Catalog number: 136194-77-9
Category: Inhibitor
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Molecular Formula:
C24H18N4O
Molecular Weight:
378.435
COA:
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Targets:
PKC
Description:
GO 6976, also known as PD-406976, is a potent inhibitor of neurotrophin-receptor intrinsic tyrosine kinase. Gö 6976 blocked neurotrophin-induced signaling and autophosphorylation of neurotrophin-specific tyrosine kinase (Trk) receptors, either Trk B in cortical neurons or Trk A in GT1-1-trk9 cells.
Purity:
0.98
Appearance:
white solid powder
Synonyms:
GO-6976; GO6976; GO 6976; PD-406976; PD 406976; PD406976.
MSDS:
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InChIKey:
VWVYILCFSYNJHF-UHFFFAOYSA-N
InChI:
InChI=1S/C24H18N4O/c1-27-17-9-4-2-7-14(17)20-21-16(13-26-24(21)29)19-15-8-3-5-10-18(15)28(12-6-11-25)23(19)22(20)27/h2-5,7-10H,6,12-13H2,1H3,(H,26,29)
Canonical SMILES:
CN1C2=CC=CC=C2C3=C4C(=C5C6=CC=CC=C6N(C5=C31)CCC#N)CNC4=O
1.Tetradecanoyl phorbol acetate induces expression of Toll-like receptor 2 in U937 cells: involvement of PKC, ERK, and NF-kappaB.
Jang BC;Jung TY;Paik JH;Kwon YK;Shin SW;Kim SP;Ha JS;Suh MH;Suh SI Biochem Biophys Res Commun. 2005 Mar 4;328(1):70-7.
Toll-like receptors (TLRs) have been identified recently as crucial signaling receptors mediating the innate immune recognition. Though induction of TLR2 or TLR4 by 12-O-tetradecanoyl phorbol 13-acetate (TPA) in leukemia cells has been reported, however, the mechanism by which TPA up-regulates TLR2 or TLR4 remains poorly understood. In this study, we investigated the effect of TPA on induction of TLR2 in U937 cells. TPA markedly induced TLR2 mRNA and protein expressions. TLR2 expression in response to TPA was attenuated by pretreatments with GF109203X and Go6976 (inhibitors of protein kinase C (PKC)) and PD98059 (an inhibitor of extracellular signal-regulated kinases (ERKs)), but not SB203580 (an inhibitor of p38s) and SP600125 (an inhibitor of c-Jun N-terminal kinases), suggesting involvement of PKC and ERKs in this response. Moreover, TPA-induced PKC activation was linked to generation of reactive oxygen species, which were dispensable for TLR2 expression in U937 cells. Pretreatments with GF109203X blocked TPA-induced phosphorylation of ERKs, suggesting activation of ERKs by PKC. In addition, TPA induced nuclear factor-kappaB (NF-kappaB) activation, which was shown by increased nuclear translocation of p65 NF-kappaB and degradation of IkappaB-alpha, a NF-kappaB inhibitory protein.
2.PKC-delta-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase.
Talior I;Tennenbaum T;Kuroki T;Eldar-Finkelman H Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E405-11. Epub 2004 Oct 26.
Oxidative stress is thought to be one of the causative factors contributing to insulin resistance and type 2 diabetes. Previously, we showed that reactive oxygen species (ROS) production is significantly increased in adipocytes from high-fat diet-induced obese and insulin-resistant mice (HF). ROS production was also associated with the increased activity of PKC-delta. In the present studies, we hypothesized that PKC-delta contributes to ROS generation and determined their intracellular source. NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) reduced ROS levels by 50% in HF adipocytes, and inhibitors of NO synthase (L-NAME, 1 mM), xanthine oxidase (allopurinol, 100 microM), AGE formation (aminoguanidine, 10 microM), or the mitochondrial uncoupler (FCCP, 10 microM) had no effect. Rottlerin, a selective PKC-delta inhibitor, suppressed ROS levels by approximately 50%. However, neither GO-6976 nor LY-333531, effective inhibitors toward conventional PKC or PKC-beta, respectively, significantly altered ROS levels in HF adipocytes. Subsequently, adenoviral-mediated expression of wild-type PKC-delta or its dominant negative mutant (DN-PKC-delta) in HF adipocytes resulted in either a twofold increase in ROS levels or their suppression by 20%, respectively.
3.Conventional protein kinase C and atypical protein kinase Czeta differentially regulate macrophage production of tumour necrosis factor-alpha and interleukin-10.
Foey AD;Brennan FM Immunology. 2004 May;112(1):44-53.
In chronic inflammatory diseases such as rheumatoid arthritis, joint macrophages/monocytes are the major source of pro- and anti-inflammatory cytokines. Little is understood regarding the signalling pathways which determine the production of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) and the anti-inflammatory cytokine, interleukin-10 (IL-10). Two pathways integral to macrophage function are the protein kinase C (PKC)- and the cAMP-dependent pathways. In this report, we have investigated the involvement of PKC and cAMP in the production of TNF-alpha and IL-10 by peripheral blood monocyte-derived macrophages. The utilization of the PKC inhibitors Go6983, Go6976 and RO-32-0432 demonstrated a role for conventional PKCs (alpha and beta) in the production of TNF-alpha in response to stimulation by lipopolysaccharide and phorbol 12-myristate 13-acetate (PMA)/ionomycin. PKC stimulation resulted in the downstream activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway which differentially regulates TNF-alpha and IL-10. The addition of cAMP however, suppressed activation of this MAPK and TNF-alpha production. Cyclic-AMP augmented IL-10 production and cAMP response element binding protein activation upon stimulation by PMA/ionomycin.
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CAS 136194-77-9 GO-6976

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