Go 6983
(Synonyms: 3-[1-[3-(二甲基氨基)丙基]-5-甲氧基-1H-吲哚-3-基]-4-(1H-吲哚-3-基)-1H-吡咯-2,5-二酮,Goe 6983;Go6983;Go-6983) 目录号 : GC16907
Inhibitor of protein kinase C
Cas No.:133053-19-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Kinase experiment [1]: | |
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Preparation Method |
Phosphorylation reactions were carried out in a total volume of 100 μl, containing buffer C, 4 mM MgCl2, 10 μg PS, 100 nM TPA, 5 ul of a Sf158 cell extract as a source of recombinant PKCu or of Sf9 cell extracts as a source of other recombinant PKC isoenzymes, 10 ug of syntide 2 as substrate, and 35 μM ATP containing 1 μCi [y-32P] ATP. In some experiments PS and TPA were omitted or various inhibitors(including Go 6983 (Gö 6983)) at concentrations were added. After incubation for 10 min at 30°C, the reaction was terminated by transferring 50 ul of the assay mixture onto a 20 mm square piece of phosphocellulose paper (Whatman p81), which was washed 3 times in deionized water and twice in acetone. |
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Reaction Conditions |
10-1-106nM Go 6983 (Gö 6983) for 10 min at 30°C |
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Applications |
Go 6983 (Gö 6983) is a pan-PKC inhibitor that acts on PKCα, PKCβ, PKCγ and PKCδ with IC50 values of 7 nM, 7 nM, 6 nM and 10 nM, respectively. Go 6983 (Gö 6983) has a weak effect on PKCζ and inhibits the activity of PKCμ. |
| Cell experiment [2]: | |
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Cell lines |
MDA-MB-231 cells |
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Preparation Method |
MDA-MB-231 cells were seeded in 96-well plates and incubated overnight. Next, various concentrations of Go 6983 (Gö 6983) (0, 0.625, 1.25, 2.5, 5, 10, 20, or 40 μM) were added to the cells to incubate for 24, 48 and 72 h. PMS (100 μL) and MTS (2 mL) were thoroughly mixed, and the resulting solution was added to each well of the 96-well plate. Finally, the optical density (OD) at 490 nm of each well was measured by using an enzyme-linked immunosorbent assay (ELISA) plate reader. |
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Reaction Conditions |
Go 6983 (Gö 6983) (0, 0.625, 1.25, 2.5, 5, 10, 20, or 40 μM) for 24, 48 and 72 h |
|
Applications |
The IC50 of Go 6983 (Gö 6983) at 24, 48, and 72 h were 58.64, 22.07, and 12.93 μM, respectively.At the concentrations used in our experiments, Go 6983 (Gö 6983) has no toxic effects on MDA-MB-231 cells. Go 6983 (Gö 6983) inhibits invasion and migration of MDA-MB-231 cells. |
| Animal experiment [3]: | |
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Animal models |
Nude mice |
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Preparation Method |
Twenty-four nude mice were divided randomly into the following four groups: Sham group, vehicle group, low dose group, and high dose group. MDA-MB-231 cells or PBS were injected into the humeral metaphysis of each mouse. After 14 days, the mice in the vehicle and sham groups were injected intraperitoneally with 100 μL of PBS, and high- and low-dose groups were injected intraperitoneally daily with 5 or 2.5 mg/kg Go 6983 (Gö 6983), respectively. All mice were sacrificed 28 days later, and tumor growth and bone destruction were observed by X-ray and microCT. The tumor tissues were examined histologically, and the long diameter, short diameter, and volume of the tumor were measured. |
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Dosage form |
5 or 2.5 mg/kg Go 6983 (Gö 6983) for 28days |
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Applications |
Go 6983 (Gö 6983) can inhibit breast cancer osteolysis in vivo. |
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References: [1]. Gschwendt M, Dieterich S,et,al.Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80. doi: 10.1016/0014-5793(96)00785-5. PMID: 8772178. |
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Go 6983 (G? 6983) is one of the bisindolylmaleimide group of PKC inhibitor compounds, Go 6983 (G? 6983) was able to differentiate between PKC mu and other PKC isoenzymes. Go 6983 (G? 6983) is a pan-PKC inhibitor that acts on PKCα, PKCβ, PKCγ and PKCδ with IC50 values of 7 nM, 7 nM, 6 nM and 10 nM, respectively. Go 6983 (G? 6983) has a weak effect on PKCζ and inhibits the activity of PKCμ[3,4].
Go 6983 (G? 6983) inhibits invasion and migration of MDA-MB-231 cells. Go 6983 (G? 6983) activates the mitochondrial apoptosis pathway in MDA-MB-231 cell. Go 6983 (G? 6983) inhibits the Src pathway in MDA-MB-231 cells and inhibits phosphorylation of PKC[2]. Platelet aggregation induced by epi was potentiated by RO 31-8220 (RO) or Go 6983 (G? 6983) [1]. Go 6983 (G? 6983) may exert cardioprotection by en- hancing endothelial NO release, which has been found to be cardioprotective in the setting of MI/R[6].
Tumor volume, long diameter, and short diameter were all lower in the mice injected with Go 6983 (G? 6983) than in those of the vehicle control group (Figures 1B D). The volume of tumors in the high dose group was approximately one-third of those in the vehicle group, indicating that Go 6983 (G? 6983) suppresses the growth and bone metastasis of breast cancer[2]. Go 6983 (G? 6983) (100 nM) significantly reduced PMN adherence to the endothelium and infiltration into the myocardium compared with I/R + PMN hearts, and significantly inhibited superoxide release from PMNs. In the presence of PMNs, Go 6983 (G? 6983) attenuated post-I/R cardiac contractile dysfunction, which may be related in part to decreased superoxide production[5]. Go 6983 (G? 6983) was able to attenuate urotensin II-induced contraction in rat aorta, in this case, through inhibition of Ca 2+/calmodulin/MLC kinase[7].
References:
[1]. Kim SY, Kim S, et,al. PKC inhibitors RO 31-8220 and G? 6983 enhance epinephrine-induced platelet aggregation in catecholamine hypo-responsive platelets by enhancing Akt phosphorylation. BMB Rep. 2011 Feb;44(2):140-5. doi: 10.5483/BMBRep.2011.44.2.140. PMID: 21345315.
[2]. Luan Z, Li J, et,al. G?6983 attenuates breast cancer-induced osteolysis by the apoptotic pathway. Cell Biol Int. 2020 Mar;44(3):838-847. doi: 10.1002/cbin.11281. Epub 2019 Dec 26. PMID: 31814221.
[3]. Gschwendt M, Dieterich S, et,al. Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80. doi: 10.1016/0014-5793(96)00785-5. PMID: 8772178.
[4]. Gschwendt M, Kittstein W, et,al. Differential effects of suramin on protein kinase C isoenzymes. A novel tool for discriminating protein kinase C activities. FEBS Lett. 1998 Jan 9;421(2):165-8. doi: 10.1016/s0014-5793(97)01530-5. PMID: 9468299.
[5]. Peterman EE, Taormina P 2nd, et,al. G? 6983 exerts cardioprotective effects in myocardial ischemia/reperfusion. J Cardiovasc Pharmacol. 2004 May;43(5):645-56. doi: 10.1097/00005344-200405000-00006. PMID: 15071351.
[6]. Omiyi D, Brue RJ, et,al. Protein kinase C betaII peptide inhibitor exerts cardioprotective effects in rat cardiac ischemia/reperfusion injury. J Pharmacol Exp Ther. 2005 Aug;314(2):542-51. doi: 10.1124/jpet.104.082131. Epub 2005 May 5. PMID: 15878997.
[7]. Tasaki K, Hori M, et,al. Mechanism of human urotensin II-induced contraction in rat aorta. J Pharmacol Sci. 2004 Apr;94(4):376-83. doi: 10.1254/jphs.94.376. PMID: 15107577.
Go 6983 (GÖ 6983) 是 PKC 抑制剂化合物的双吲哚基马来酰亚胺组之一，Go 6983 (GÖ 6983) 能够区分 PKC mu 和其他 PKC 同工酶。 Go 6983 (GÖ 6983) 是一种泛 PKC 抑制剂，作用于 PKCα、PKCβ、PKCγ 和 PKCδ，IC50 值分别为 7 nM、7 nM、6 nM 和 10 nM。 Go 6983 (GÖ 6983) 对PKCζ的作用较弱，抑制PKCμ[3,4]的活性。
Go 6983 (GÖ 6983) 抑制 MDA-MB-231 细胞的侵袭和迁移。 Go 6983 (GÖ 6983) 激活 MDA-MB-231 细胞中的线粒体凋亡通路。 Go 6983 (GÖ 6983) 抑制 MDA-MB-231 细胞中的 Src 通路并抑制 PKC[2] 的磷酸化。 RO 31-8220 (RO) 或 Go 6983 (GÖ 6983) [1] 增强了 epi 诱导的血小板聚集。 Go 6983 (GÖ 6983) 可能通过增强内皮细胞释放 NO 来发挥心脏保护作用，这已被发现在 MI/R 的情况下具有心脏保护作用[6]。
注射 Go 6983 (GÖ 6983) 的小鼠的肿瘤体积、长径和短径均低于载体对照组（图 1B D）。高剂量组的肿瘤体积约为载体组的三分之一，表明 Go 6983（GÖ 6983）抑制了乳腺癌的生长和骨转移[2]。与 I/R + PMN 心脏相比，Go 6983 (GÖ 6983) (100 nM) 显着降低了 PMN 对内皮的粘附和对心肌的浸润，并显着抑制了 PMN 的超氧化物释放。在 PMN 存在的情况下，Go 6983 (GÖ 6983) 减轻了 I/R 后心脏收缩功能障碍，这可能部分与超氧化物生成减少有关[5]。 Go 6983 (GÖ 6983) 能够减弱 urotensin II 诱导的大鼠主动脉收缩，在这种情况下，通过抑制 Ca 2+/钙调蛋白/MLC 激酶[7]。
| Cas No. | 133053-19-7 | SDF | |
| 别名 | 3-[1-[3-(二甲基氨基)丙基]-5-甲氧基-1H-吲哚-3-基]-4-(1H-吲哚-3-基)-1H-吡咯-2,5-二酮,Goe 6983;Go6983;Go-6983 | ||
| 化学名 | 3-[1-[3-(dimethylamino)propyl]-5-methoxyindol-3-yl]-4-(1H-indol-3-yl)pyrrole-2,5-dione | ||
| Canonical SMILES | CN(C)CCCN1C=C(C2=C1C=CC(=C2)OC)C3=C(C(=O)NC3=O)C4=CNC5=CC=CC=C54 | ||
| 分子式 | C26H26N4O3 | 分子量 | 442.51 |
| 溶解度 | ≥ 22.15mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2598 mL | 11.2992 mL | 22.5984 mL |
| 5 mM | 0.452 mL | 2.2598 mL | 4.5197 mL |
| 10 mM | 0.226 mL | 1.1299 mL | 2.2598 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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G? 6983: a fast acting protein kinase C inhibitor that attenuates myocardial ischemia/reperfusion injury
Reperfusion injury is characterized by a decrease in endothelial release of nitric oxide within 5 min after reperfusion, increased leukocyte-endothelium interaction, and transmigration of leukocytes into the myocardium, producing cardiac contractile dysfunction. G? 6983 is a fast acting, lipid soluble, broad spectrum protein kinase C inhibitor. When administered at the beginning of reperfusion, it can restore cardiac function within 5 min and attenuate the deleterious effects associated with acute ischemia/reperfusion. G? 6983 may offer greater cardioprotection than other broad-spectrum PKC inhibitors in postischemic reperfusion injury because it inhibits PKC(zeta) as well as four other isoforms. The cardioprotection is associated with decreased leukocyte superoxide release and increased endothelial derived nitric oxide from vascular tissue. In vitro studies of human tissue showed that G? 6983 significantly inhibited antigen-induced superoxide release from leukocytes of patients previously sensitized to tree pollen. In human vascular tissue, G? 6983 inhibited intracellular Ca(2+) accumulation, suggesting a mechanism for its vasodilator properties. These studies suggest that G? 6983 would be an effective compound to use in a clinical ischemia/reperfusion setting of organ transplantation and/or cerebral ischemia where inhibiting superoxide release and vasoconstriction in postischemic tissues would allow for better restoration of organ function during reperfusion. However, given the broad-spectrum action of G? 6983, careful titration of the dose regimen would be recommended to ensure a successful outcome in the setting of organ transplantation and/or cerebral ischemia.
G? 6983 exerts cardioprotective effects in myocardial ischemia/reperfusion
Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction. Inhibiting protein kinase C (PKC) inhibits the release of superoxide from PMNs. The compound G? 6983 is an inhibitor of all five PKC isoforms present in PMNs. Therefore, we hypothesized that G? 6983 could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production from PMNs. We studied isolated rat hearts following ischemia (20 minutes) and reperfusion (45 minutes) infused with activated PMNs. In hearts reperfused with PMNs and G? 6983 (100 nM, n = 7), left ventricular developed pressure (LVDP) and the rate of LVDP (+dP/dt max) recovered to 89 +/- 7% and 74 +/- 2% of baseline values, respectively, at 45 minutes postreperfusion compared with I/R hearts (n = 9) receiving PMNs alone, which only recovered to 55 +/- 3% and 45 +/- 5% of baseline values for LVDP and +dP/dtmax, respectively (P < 0.01). G? 6983 (100 nM) significantly reduced PMN adherence to the endothelium and infiltration into the myocardium compared with I/R + PMN hearts (P < 0.01), and significantly inhibited superoxide release from PMNs by 90 +/- 2% (P < 0.01). In the presence of PMNs, G? 6983 attenuated post-I/R cardiac contractile dysfunction, which may be related in part to decreased superoxide production.
PKC inhibitors RO 31-8220 and G? 6983 enhance epinephrine-induced platelet aggregation in catecholamine hypo-responsive platelets by enhancing Akt phosphorylation
Impaired responsiveness of platelets to epinephrine (epi) and other catecholamines (CA) has been reported in approximately 20% of the healthy Korean and Japanese populations. In the present study, platelet aggregation induced by epi was potentiated by RO 31-8220 (RO) or G? 6983 (G?). Phosphorylated Akt (p-Akt) was very low in epi-stimulated PRP from CA-hypo-responders (CA-HY), whereas it was detected in those from CA-good responders (CA-GR). RO and G? increased p-Akt, one of the major downstream effectors of phosphoinositol-3 kinase (PI3K), in epi-stimulated PRP from both groups. Wortmannin, a PI3K inhibitor, attenuated the RO or G?-induced potentiation of p-Akt in epi-stimulated PRP, suggesting positive effects for RO and G? on PI3K. TXA(2) formation was increased by the addition of either RO or G? in epi-stimulated platelets. The present data also suggest that impaired Akt phosphorylation may be responsible for epinephrine hypo-responsiveness of platelets.
Improved synergistic anticancer efficacy of quercetin in combination with PI-103, rottlerin, and G0 6983 against MCF-7 and RAW 264.7 cells
Flavonoids have been chronicles of the history of a long way journey in the cure of physiological or pathophysiological conditions in various diseases including cancer. Our previous findings suggest the extensive mechanism of quercetin (QUE) mediated regression of cell survival, cell proliferation, oxidative stress, inflammation, and angiogenesis via modulating PI3K and PKC signaling in lymphoma as well as hepatocellular carcinoma. PI3K-PKC pathway is a key monitor of mammalian cells regulated by its different isoenzymes, which may exert similar or opposite cellular effects by differential coupling of signaling pathways. Put forward the invention of selective inhibitors against various isoenzymes is beneficial to reduce the burden of inclusive deleterious effects of drug for normal physiological process. Therefore, we hypothesized the improved anticancer efficacy of QUE in combination with isoenzyme inhibitors-rottlerin (ROT-PKCδ inhibitor), G0 6983 (PKCα inhibitor), and PI-103 (p110α-class I PI3K inhibitor) in MCF-7 and RAW 264.7 cells. QUE significantly improves the cytotoxicity of ROT + G0 6983 ranged 30-55% and PI-103 ranged 24-63% after 24-48 h against MCF-7 cells. Additionally in the presence of QUE, the improved cytotoxicity of ROT + G0 6983 is observed to range 69-75% and PI-103 ranged 45-88% after 24-48 h in RAW 264.7 cells. This increment in cell deaths are positively correlated with enhanced morphological alteration observed in MCF-7 cells. Further, QUE significantly increases the attenuation of PKCα level approximately by 50% in combination with PI-103. Overall results of the current study suggested that QUE improves the synergistic anticancer efficacy in combination with PI-103, ROT, and G0 6983 in MCF-7 and RAW 264.7 cells.
Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling
Background: Hydrogen peroxide (H?O?)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations.
Methods: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H?O? (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, G? 6983 (1 μM), was applied to test the involvement of PKC.
Results: H?O? perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with G? 6983 prevented the emergence of H?O?-induced afterdepolarizations. Additional application of G? 6983 with H?O? effectively suppressed H?O?-induced afterdepolarizations. H?O? increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by G? 6983 (p < 0.01). H?O? also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, G? 6983 showed little effect on H?O?-induced enhancement of Ito.
Conclusions: H?O? induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.