SB 202190 is a selective p38 MAP kinase inhibitor with IC50s of 50 nM and 100 nM for p38α and p38β2, respectively. SB 202190 binds to the ATP pocket of the active recombinant human p38 kinase with a Kd of 38 nM. SB 202190 has anti-cancer activity and rescued memory deficits[1,2]. SB202190 inhibits apoptosis of endothelial cells by inducing autophagy and heme oxidase 1 [3].
SB 202190(50 μM;24 hours) significantly inhibits both basal and anti-Fas antibody-induced MAPKAPK 2 activity in a dose-dependent manner. SB202190 by itself is sufficient to induce cell death in Jurkat and HeLa cells through activation of CPP32-like caspases, which can be blocked by expression of bcl-2. SB202190-induced apoptosis is attenuated by p38β but augmented by p38α[4]. SB 202190 treatment(5/10 μM SB202190;4h) induces phosphorylation of JNK in a dose- and time- dependent manner in A549 cells, induces phosphorylation of ATF-2 transcription factor, and increases AP-1 DNA binding[5]. SB 202190(5μM;1h) strongly inhibits UVB induced COX-2 protein expression in HaCaT cells, and markedly inhibits UVB induced cox-2 mRNA[6].
SB 202190(12.5 μg; i.d.) attenuated blister formation induced by human poliomyelitis IgG(PV-IgG) in a passively transferred mouse model by inhibiting p38[7]. Inhibition of P38-MAPK by SB-202190(2.5μM/kg;24d; s.c.) resulted in increased primary tumor growth in tumor-bearing Balb-c mice (4T-1 cells) [8].
SB 202190是一种选择性p38 MAP激酶抑制剂,对p38α和p38β2的IC50分别为50 nM和100 nM。SB 202190与活性重组人p38激酶的ATP口袋结合,Kd为38 nM。SB 202190具有抗癌活性和挽救记忆缺陷[1,2]。SB202190通过诱导自噬和血红素氧化酶1抑制内皮细胞凋亡[3]。
SB 202190(50 μM;24 h)显著抑制基础抗体和抗FAS抗体诱导的MAPKAPK 2活性,并呈剂量依赖性。SB202190本身足以通过激活CPP32-like caspases在Jurkat和HeLa细胞中诱导细胞死亡,可被bcl-2的表达阻断。SB202190诱导的细胞凋亡被p38β减弱,但被p38α增强[4]。SB202190处理(5/10 μM SB202190;4h)以剂量和时间依赖的方式诱导A549细胞JNK磷酸化,诱导ATF-2转录因子磷酸化,增加AP-1 DNA结合[5]。SB 202190(5μM;1h)强烈抑制UVB诱导的HaCaT细胞COX-2蛋白表达,并显著抑制UVB诱导的COX-2 mRNA[6]。
SB 202190(12.5 μg; i.d.)通过抑制p38在被动转移小鼠模型中减弱人脊髓灰质炎IgG(PV-IgG)诱导的水疱形成[7]。SB-202190对P38-MAPK的抑制作用(2.5μM/kg;24d;s.c.)导致荷瘤Balb-c小鼠(4T-1细胞)中原发肿瘤生长增加[8]。
参考文献:
[1]. Davies SP, Reddy H, et,al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. doi: 10.1042/0264-6021:3510095. PMID: 10998351; PMCID: PMC1221339.
[2]. Schwartz M, B?ckmann S, et,al.SB202190 inhibits endothelial cell apoptosis via induction of autophagy and heme oxygenase-1. Oncotarget. 2018 May 1;9(33):23149-23163. doi: 10.18632/oncotarget.25234. PMID: 29796178; PMCID: PMC5955409.
[3]. Grossi V, Liuzzi M, et,al.Sorafenib inhibits p38α activity in colorectal cancer cells and synergizes with the DFG-in inhibitor SB202190 to increase apoptotic response. Cancer Biol Ther. 2012 Dec;13(14):1471-81. doi: 10.4161/cbt.22254. Epub 2012 Sep 17. PMID: 22986232; PMCID: PMC3542239.
[4]. Nemoto S, Xiang J, et,al.Induction of apoptosis by SB202190 through inhibition of p38beta mitogen-activated protein kinase. J Biol Chem. 1998 Jun 26;273(26):16415-20. doi: 10.1074/jbc.273.26.16415. PMID: 9632706.
[5]. Muniyappa H, Das KC. Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. Cell Signal. 2008 Apr;20(4):675-83. doi: 10.1016/j.cellsig.2007.12.003. Epub 2007 Dec 8. PMID: 18222647; PMCID: PMC2423944.
[6]. Chen W, Tang Q, et,al.Role of p38 MAP kinases and ERK in mediating ultraviolet-B induced cyclooxygenase-2 gene expression in human keratinocytes. Oncogene. 2001 Jun 28;20(29):3921-6. doi: 10.1038/sj.onc.1204530. PMID: 11439356.
[7]. Berkowitz P, Hu P, et,al. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12855-60. doi: 10.1073/pnas.0602973103. Epub 2006 Aug 14. PMID: 16908851; PMCID: PMC1568937.
[8]. O'Sullivan AW, Wang JH, et,al. p38 MAP kinase inhibition promotes primary tumour growth via VEGF independent mechanism. World J Surg Oncol. 2009 Nov 15;7:89. doi: 10.1186/1477-7819-7-89. PMID: 19912664; PMCID: PMC2785811.
| Kinase experiment[1]: | |
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Preparation Method |
The p38α and p38β are assayed in 25 mM Tris-HCl, pH 7.5, containing 0.1 mM EGTA, with myelin basic protein (0.33 mg/mL) as substrate. Assays are performed either manually for 10 minutes at 30℃ in 50 μL incubations using [γ-33P]ATP, or with a Biomek 2000 Laboratory Automation Workstation in a 96-well format for 40 minutes at ambient temperature in 25 μL incubations using [γ-33P]ATP. The concentrations of ATP and magnesium acetate are 0.1 mM and 10 mM respectively. All assays are initiated with MgATP. Manual assays are terminated by spotting aliquots of incubation on to phosphocellulose paper, followed by immersion in 50 mM phosphoric acid. Robotic assays are terminated by the addition of 5 μL of 0.5 M phosphoric acid before spotting aliquots on to P30 filter mats. All papers are then washed four times in 50 mM phosphoric acid to remove ATP, once in acetone (manual incubations) or methanol (robotic incubations), and then dried and counted for radioactivity. |
|
Applications |
SB 202190 is a selective p38 MAPK inhibitor with IC50 of p38α and p38β2 at 50 nM and 100 nM, respectively. |
| Cell experiment [2]: | |
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Cell lines |
Jurkat and HeLa cells |
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Preparation Method |
Cells are serum-starved and then treated with different concentration of SB 202190 for 24 hours. Cell viability is assayed by either trypan blue exclusion or propidium iodide exclusion followed by flow cytometry analysis. The apoptotic nuclei are visualized by H33258 staining. |
|
Reaction Conditions |
50 μM;24 hours |
|
Applications |
SB202190 by itself is sufficient to induce cell death in Jurkat and HeLa cells through activation of CPP32-like caspases, which can be blocked by expression of BCL-2. |
| Animal experiment [3]: | |
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Animal models |
C57BL/6J mice |
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Preparation Method |
Neonatal C57BL/6J mice were injected i.d. with either PV IgG (1.5 mg of IgG/g body weight) or PV IgG (1.5 mg of IgG/g body weight) plus SB202190 |
|
Dosage form |
12.5 μg; i.d. |
|
Applications |
SB 202190 attenuated blister formation induced by human poliomyelitis IgG(PV-IgG) in a passively transferred mouse model by inhibiting p38. |
|
参考文献: [1]. Davies SP, Reddy H, et,al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. doi: 10.1042/0264-6021:3510095. PMID: 10998351; PMCID: PMC1221339. [2].Nemoto S, Xiang J, et,al.Induction of apoptosis by SB202190 through inhibition of p38beta mitogen-activated protein kinase. J Biol Chem. 1998 Jun 26;273(26):16415-20. doi: 10.1074/jbc.273.26.16415. PMID: 9632706. [3]. Berkowitz P, Hu P, et,al. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12855-60. doi: 10.1073/pnas.0602973103. Epub 2006 Aug 14. PMID: 16908851; PMCID: PMC1568937. | |
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