GF 109203X (Bisindolylmaleimide I)
(Synonyms: Gö 6850;Bisindolylmaleimide I) 目录号 : GC15431
GF 109203X是蛋白激酶C的选择性抑制剂，对蛋白激酶C的α和β1亚型具有选择性，对α、β1、δ、ε和ζ亚型的IC50值分别为0.0084、0.0180、0.210、0.132和5.8μM。GF 109203X可选择性抑制MLCK、PKG、PKA （IC50分别为0.6, 4.6, and 33μM）。
Cas No.:133052-90-1
Sample solution is provided at 25 µL, 10mM.
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GF 109203X is a selective inhibitor of protein kinase C, selective for the α and β1 isoforms with IC50 values of 0.0084, 0.0180, 0.210, 0.132, and 5.8μM for α, β1, δ, ε and ζ isoforms of protein kinase C respectively[1]. GF 109203X selectively inhibits over MLCK, PKG, and PKA (IC50 values are 0.6, 4.6, and 33μM respectively). GF 109203X is also an antagonist at the 5-HT3 receptor with a Ki of 29.5nM[2]. GF 109203X shows an anti-inflammatory effect targeting human neutrophils in vivo[3].
In vitro, inhibition of PKC by GF 109203X (1μM; 1h) activates GSK-3, whereas activation of PKC by phorbol-12,13-butyrate inhibits GSK-3[4]. Inhibition of protein kinase C with GF 109203X (3μM; 6h)resulted in concentration-dependent but partial inhibition of [(35)S]sulfate incorporation accompanied by a reduction in the particle size of biglycan and decorin[5]. PKC inhibitor GF 109203X (1μM; 5min) did not inhibit KCl-induced tonic force and myosin light chain (MLC) phosphorylation in rabbit artery[6].
In vivo, ventricular co-injection of wortmannin and GF 109203X (WT/GFX) (10μM and 100μM; once; i.p) can induce tau hyperphosphorylation and memory impairment of rats through activation of GSK-3[7]. GF 109203X (0.3pg/site; once; local injection) impaired memory reconsolidation in the presence of spermidine (200pmol/site)[8].
References:
[1] Toullec, D et al. “The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.” *The Journal of biological chemistry* vol. 266,24 (1991): 15771-81.
[2] Coultrap, S J et al. “Competitive antagonism of the mouse 5-hydroxytryptamine3 receptor by bisindolylmaleimide I, a "selective" protein kinase C inhibitor.” *The Journal of pharmacology and experimental therapeutics* vol. 290,1 (1999): 76-82.
[3] Cabanis, A et al. “Effect of the protein kinase C inhibitor GF 109 203X on elastase release and respiratory burst of human neutrophils.” *General pharmacology* vol. 27,8 (1996): 1409-14. doi:10.1016/s0306-3623(96)00053-5
[4] Wang, Ze-Fen et al. “Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture.” *Journal of neurochemistry* vol. 98,4 (2006): 1167-75. doi:10.1111/j.1471-4159.2006.03956.x
[5] Ivey, Melanie E, and Peter J Little. “Thrombin regulates vascular smooth muscle cell proteoglycan synthesis via PAR-1 and multiple downstream signalling pathways.” *Thrombosis research* vol. 123,2 (2008): 288-97. doi:10.1016/j.thromres.2008.04.019
[6] Urban, Nicole H et al. “K+ depolarization induces RhoA kinase translocation to caveolae and Ca2+ sensitization of arterial muscle.” *American journal of physiology. Cell physiology* vol. 285,6 (2003): C1377-85. doi:10.1152/ajpcell.00501.2002
[7] Liu, Shi Jie et al. “Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory.” *Journal of neurochemistry* vol. 87,6 (2003): 1333-44. doi:10.1046/j.1471-4159.2003.02070.x
[8] Girardi, Bruna Amanda et al. “Spermidine-induced improvement of reconsolidation of memory involves calcium-dependent protein kinase in rats.” *Learning & memory (Cold Spring Harbor, N.Y.)* vol. 23,1 21-8. 15 Dec. 2015, doi:10.1101/lm.039396.115
GF 109203X是蛋白激酶C的选择性抑制剂，对蛋白激酶C的α和β1亚型具有选择性，对α、β1、δ、ε和ζ亚型的IC50值分别为0.0084、0.0180、0.210、0.132和5.8μM。GF 109203X可选择性抑制MLCK、PKG、PKA （IC50分别为0.6, 4.6, and 33μM）[1]。GF 109203X也是5-HT3受体的拮抗剂，Ki值为29.5nM[2]。GF 109203X在体内具有针对人中性粒细胞的抗炎作用[3]。
在体外，GF 109203X (1μM; 1h) 对PKC的抑制作用并激活GSK-3，而phorhol -12,13-butyrate激活PKC则抑制GSK-3[4]。GF 109203X (3μM; 6h) 对蛋白激酶C的抑制作用导致[(35)S]硫酸盐融入的浓度依赖但部分抑制作用，同时导致biglycan和decorin的颗粒大小减小[5]。PKC抑制剂GF 109203X (1μM; 5min) 不抑制KCl诱导的兔动脉强直力和肌球蛋白轻链（MLC）磷酸化[6]。
在体内，wortmannin与GF-109203X (WT/GFX) (10μM and 100μM; 单次; 腹腔注射) 可通过激活GSK-3诱导tau过度磷酸化和大鼠记忆障碍[7]。GF 109203X (0.3pg/site; 单次; 原位注射)损伤在亚精胺（200pmol/site）存在时的记忆巩固[8]。
| Cell experiment [1]: | |
Cell lines | N2a cells |
Preparation Method | Cells treated with and without GF 109203X (1μM; 1h) were collected and homogenized in 10mM Tris, 150mM NaCl, 2mM EGTA, 2mM dithiothreitol (DTT), 0.1mM Na2VO4 and protease inhibitors. The cell homogenates were centrifuged at 18000g for 15min at 4°C and protein concentration in the supernatants was determined. GSK-3 activity was measured using phospho-GS peptide 2. 7.5μg protein was incubated in 25μl buffer containing 30mM Tris, 10mM MgCl, 10mM NaF, 1mM Na2VO4, 2mM EGTA, 10mM B-mercaptoethanol, 200μM γ-[32P]ATP (1500cm/pmol ATP) and 20μM phospho-GS peptide 2 with pH 7.4 at 30°C for 30min. The reaction was stopped with 25μl 300mM phosphoric acid. After washing out the free 32P with PBS three times, half of the incubation mixture was used for liquid scintillation counting analysis. Enzyme activities were calculated as pmoles of phosphate incorporated per milligram of protein per minute at 30°C and expressed as activity relative to control. |
Reaction Conditions | 1μM; 1h |
Applications | inhibition of PKC by GF 109203X (1μM; 1h) activates GSK-3, whereas activation of PKC by phorbol-12,13-butyrate inhibits GSK-3 |
| Animal experiment [2]: | |
Animal models | Male Wistar rats |
Preparation Method | Each rat was first anesthetized by chloral hydrate [30mg/kg, intraperitoneally (i.p.)] and placed on a stereotactic instrument with the incisor bar set 2mm below the ear bars (i.e. flat skull). A 50-lL syringe was stereotactically placed into the left ventricle at the co-ordinates for bregma and dura of AP-0.8, L-1.5 and V-4 (in mm) after the scalp was incised and retracted. Different concentrations of wortmannin or GF 109203X or LiCl, separately or in combination, in a total volume of 10μL were injected into each rat using artificial cerebrospinal fluid (aCSF) containing 140mM NaCl, 3.0mM KCl, 2.5mM CaCl2, 1.0mM MgCl2, 1.2mM Na2HPO4, pH7.4, as vehicle . All surgical procedures were completed under sterile conditions and penicillin [200000U, intramuscularly (i.m.)] was injected to prevent infection. |
Dosage form | 10μM and 100μM; once; i.p |
Applications | ventricular co-injection of wortmannin and GF 109203X (WT/GFX) can induce tau hyperphosphorylation and memory impairment of rats through activation of GSK-3 |
References: | |
| Cas No. | 133052-90-1 | SDF | |
| 别名 | Gö 6850;Bisindolylmaleimide I | ||
| 化学名 | 3-[1-[3-(dimethylamino)propyl]indol-3-yl]-4-(1H-indol-3-yl)pyrrole-2,5-dione | ||
| Canonical SMILES | CN(C)CCCN1C=C(C2=CC=CC=C21)C3=C(C(=O)NC3=O)C4=CNC5=CC=CC=C54 | ||
| 分子式 | C25H24N4O2 | 分子量 | 412.49 |
| 溶解度 | ≥ 20.6mg/mL in DMSO | 储存条件 | 4°C, protect from light |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4243 mL | 12.1215 mL | 24.243 mL |
| 5 mM | 0.4849 mL | 2.4243 mL | 4.8486 mL |
| 10 mM | 0.2424 mL | 1.2122 mL | 2.4243 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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