更新于：2024-11-01

Akt x PKC x PAK1

更新于：2024-11-01

基本信息

关联

项与 Akt x PKC x PAK1 相关的药物

CHS-111

靶点

Akt x PAK1 x PKC

作用机制

Akt 刺激剂 [+2]

在研机构

中山医学大学

原研机构

中山医学大学

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Akt x PKC x PAK1 相关的临床结果

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100 项与 Akt x PKC x PAK1 相关的转化医学

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0 项与 Akt x PKC x PAK1 相关的专利（医药）

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项与 Akt x PKC x PAK1 相关的文献（医药）

2013-02-01·European Journal of Pharmacology3区 · 医学

Inhibition of formyl peptide-stimulated superoxide anion generation by Fal-002-2 occurs mainly through the blockade of the p21-activated kinase and protein kinase C signaling pathways in ratneutrophils

3区 · 医学

Article

作者: Yun-Jie Hung ; Jih-Pyang Wang ; Sheng-Chu Kuo ; Mei-Feng Hsu ; Miau-Rong Lee ; Ya-Ru Tsai ; Hui-Yi Lin ; Li-Jiau Huang

In formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils, a synthetic compound, 6-chloro-2-(2-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Fal-002-2), inhibited superoxide anion (O2(•-)) generation with an IC50 value of about 11μM, which was not mediated by scavenging the generated O2(•-) or by a cytotoxic effect on neutrophils. Fal-002-2 effectively attenuated the phosphorylation of Ser residues in p47(phox) and the association between p47(phox) and p22(phox) in fMLP-stimulated neutrophils. The interaction of p47(phox) with protein kinase C (PKC) isoforms (α, βI, βII, δ and ζ) was attenuated by Fal-002-2 with a similar IC50 value to that required for inhibition of O2(•-) generation, whereas Fal-002-2 had no prominent effect on PKC isoform membrane translocation and did not affect the kinase activity. Moreover, Fal-002-2 had no effect on the phosphorylation of Akt and downstream glycogen synthase kinase-3β, only slightly affected the intracellular free Ca(2+) concentration, phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase (MAPK), but effectively attenuated the downstream MAPK-activated protein kinase-2 phosphorylation. The interaction of p21-activated kinase (PAK) 1with p47(phox), phosphorylation of PAK1 (Thr423/Ser144) and the membrane recruitment of PAK1 were effectively inhibited by Fal-002-2. Fal-002-2 also blocked the activation of Rac1 and Cdc42 in a concentration range that effectively inhibited PAK activation. Taken together, these results suggest that Fal-002-2 inhibits fMLP-stimulated O2(•-) generation in neutrophils mainly through the blockade of PKC and PAK signaling pathways and partly through p38 MAPK signaling.

2012-05-01·European Journal of Pharmacology3区 · 医学

The signaling mechanisms mediating the inhibitory effect of TCH-1116 on formyl peptide-stimulated superoxide anion generation in neutrophils

3区 · 医学

Article

作者: Jih-Pyang Wang ; Mei-Feng Hsu ; Sheng-Chu Kuo ; Yeh-Long Chen ; Ya-Ru Tsai ; Cherng-Chyi Tzeng ; Miau-Rong Lee ; Li-Jiau Huang

In fMLP (formyl-Met-Leu-Phe)-stimulated rat neutrophils, a mixture of regioisomers benzo[a]furo[2,3-c]phenazine-10-carboxylic acid and benzo[a]furo[2,3-c]phenazine-11-carboxylic acid (TCH-1116) inhibited O(2)(-) (superoxide anion) generation, which was not mediated by scavenging the generated O(2)(-) or by a cytotoxic effect on neutrophils. TCH-1116 had no effect on the arachidonic acid-induced NADPH oxidase activation in a cell-free system, whereas it effectively attenuated the phosphorylation of Ser residues in p47(phox) and the association between p47(phox) and p22(phox) in fMLP-stimulated neutrophils. The interaction of p47(phox) with PKC (protein kinase C) isoforms (α, βI, βII, δ and ζ) was attenuated by TCH-1116, whereas TCH-1116 did not affect the PKC isoforms membrane translocation, phosphorylation (Ser660) and kinase activity. TCH-1116 effectively attenuated the association between PKB/Akt (protein kinase B) and p47(phox), Akt phosphorylation (Thr308/Ser473) and kinase activities of Akt and human recombinant PDK (3-phosphoinositide-dependent kinase) 1, whereas it had no effect on recruitment of Akt, phospho-PDK1 (Ser241) and p110γ to membrane. Moreover, the interaction of p21-activated kinase (PAK) 1 with p47(phox) and the phosphorylation of PAK1 (Thr423 but not Ser144) were inhibited by TCH-1116, but without affecting the membrane recruitment of PAK1. The cellular cyclic AMP level was not changed by TCH-1116. Taken together, these results suggest that TCH-1116 inhibits fMLP-stimulated O(2)(-) generation in rat neutrophils through the blockade of PKC, Akt and PAK signaling pathways.

2011-01-01·Journal of Cellular Biochemistry3区 · 生物学

Profiling the changes in signaling pathways in ascorbic acid/β‐glycerophosphate‐induced osteoblastic differentiation

3区 · 生物学

Article

作者: Maikel P. Peppelenbosch ; Renato Milani ; Edgar Julian Paredes-Gamero ; Giselle Zenker Justo ; Carmen Verissima Ferreira ; Antonio Hernandes Chaves Neto ; Karla Cristiana Queiroz

AbstractDespite numerous reports on the ability of ascorbic acid and β‐glycerophosphate (AA/β‐GP) to induce osteoblast differentiation, little is known about the molecular mechanisms involved in this phenomenon. In this work, we used a peptide array containing specific consensus sequences (potential substrates) for protein kinases and traditional biochemical techniques to examine the signaling pathways modulated during AA/β‐GP‐induced osteoblast differentiation. The kinomic profile obtained after 7 days of treatment with AA/β‐GP identified 18 kinase substrates with significantly enhanced or reduced phosphorylation. Peptide substrates for Akt, PI3K, PKC, BCR, ABL, PRKG1, PAK1, PAK2, ERK1, ERBB2, and SYK showed a considerable reduction in phosphorylation, whereas enhanced phosphorylation was observed in substrates for CHKB, CHKA, PKA, FAK, ATM, PKA, and VEGFR‐1. These findings confirm the potential usefulness of peptide microarrays for identifying kinases known to be involved in bone development in vivo and in vitro and show that this technique can be used to investigate kinases whose function in osteoblastic differentiation is poorly understood. J. Cell. Biochem. 112: 71–77, 2011. © 2010 Wiley‐Liss, Inc.