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].
参考文献:
[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 (G? 6983) 是 PKC 抑制剂化合物的双吲哚基马来酰亚胺组之一，Go 6983 (G? 6983) 能够区分 PKC mu 和其他 PKC 同工酶。 Go 6983 (G? 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 (G? 6983) 对PKCζ的作用较弱，抑制PKCμ[3,4]的活性。
Go 6983 (G? 6983) 抑制 MDA-MB-231 细胞的侵袭和迁移。 Go 6983 (G? 6983) 激活 MDA-MB-231 细胞中的线粒体凋亡通路。 Go 6983 (G? 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 (G? 6983) [1] 增强了 epi 诱导的血小板聚集。 Go 6983 (G? 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 (G? 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（G? 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 (G? 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 (G? 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 (G? 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]。
| 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 (G? 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 (G? 6983) for 10 min at 30°C |
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Applications |
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. |
| 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 (G? 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 (G? 6983) (0, 0.625, 1.25, 2.5, 5, 10, 20, or 40 μM) for 24, 48 and 72 h |
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Applications |
The IC50 of Go 6983 (G? 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 (G? 6983) has no toxic effects on MDA-MB-231 cells. Go 6983 (G? 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 (G? 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 (G? 6983) for 28days |
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Applications |
Go 6983 (G? 6983) can inhibit breast cancer osteolysis in vivo. |
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参考文献: [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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