Target Validation Information | |||||
---|---|---|---|---|---|
Target ID | T40097 | ||||
Target Name | Mitogen-activated protein kinase 8 | ||||
Target Type | Clinical Trial |
||||
Drug Potency against Target | AM-111 | Drug Info | IC50 < 500 nM | [552998] | |
NM-PP1 | Drug Info | IC50 = 140 nM | [529039] | ||
N-(6-ethoxypyridin-2-yl)acetamide | Drug Info | IC50 = 750 nM | [528237] | ||
2-(2-(butylamino)pyrimidin-4-ylamino)benzoic acid | Drug Info | IC50 = 2600 nM | [528524] | ||
2-(2-propoxypyrimidin-4-ylamino)benzoic acid | Drug Info | IC50 = 2300 nM | [528524] | ||
2-(2-(phenylamino)pyrimidin-4-ylamino)benzamide | Drug Info | IC50 = 590 nM | [528524] | ||
2-(2-(pentyloxy)pyrimidin-4-ylamino)benzoic acid | Drug Info | IC50 = 1100 nM | [528524] | ||
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide | Drug Info | Ki = 1900 nM | [528237] | ||
N-(4-amino-6-butoxy-5-cyanopyridin-2-yl)acetamide | Drug Info | IC50 = 2100 nM | [528237] | ||
2-(2-sec-butoxypyrimidin-4-ylamino)benzoic acid | Drug Info | IC50 = 700 nM | [528524] | ||
AS-601245 | Drug Info | IC50 = 2600 nM | [529039] | ||
N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)acetamide | Drug Info | IC50 = 840 nM | [528318] | ||
2-(2-phenoxypyrimidin-4-ylamino)benzoic acid | Drug Info | IC50 = 300 nM | [528524] | ||
2-(2-butoxypyrimidin-4-ylamino)benzoic acid | Drug Info | IC50 = 1900 nM | [528524] | ||
CC-401 | Drug Info | IC50 = 10000 nM | [552744] | ||
Action against Disease Model | AM-111 | AM-111 blocked JNK mediated phosphorylation and activation of transcription factors c-Jun and c-Fos. AM-111 has been shown to prevent loss of hearing using a guinea pig model inthe setting of systemic aminoglycoside administration as well as in the setting of acute acoustic tra uMa. Hearing preservation has also been noted with AM-111 when given after exposure to impulse noise tra uMa in chinchillas. | [552990] | Drug Info | |
The Effect of Target Knockout, Knockdown or Genetic Variations | Combined JNK1/JNK2 deficiency drastically increased basal glycerol release, whereas individual JNK1- or JNK2-deficiency had no effect, indicating that JNK1/JNK2-deficiency enhances basal lipolysis, whereas the alternate subtype compensates for a single JNK subtype deficiency in the regulation of basal lipolysis. The profoundly increased glycerol release associated with JNK1/JNK2-deficiency was not accompanied by a concomitant increase in NEFA release over time. In addition, JNK1-deficiency, but not JNK2-deficiency, drastically decreased NEFA release as compared with thatin JNK-intact cells, a result of increased NEFA re-esterification. In microarray, quantitative RT-PCR and western blotting, JNK1-, JNK2- and JNK1/JNK2-deficiencies selectively upregulated many genes involved in NEFA management, without affecting the expression of genes involved in insulin signalling. Assays using reporter genes driven by peroxisome proliferator-activated receptor gamma (PPAR-gamma)-responsive promoters indicate distinct roles for JNK1 and JNK2 in regulating the transcriptional effects of PPAR-gamma.While JNK1 and JNK2 have shared roles in the regulation of basal lipolysis, JNK1 has a more profound role in supporting baseline NEFA release. Inhibition of JNK1 activity in adipocytes has potential therapeutic uses for management of elevated circulating NEFA levels at the onset of insulin resistance. | [552998] | |||
References | |||||
Ref 552998 | c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim Biophys Acta. 2010 Mar;1804(3):463-75. doi: 10.1016/j.bbapap.2009.11.002. Epub 2009 Nov 10. | ||||
Ref 529039 | Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. | ||||
Ref 528237 | J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 528237 | J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. | ||||
Ref 528237 | J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 529039 | Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. | ||||
Ref 552990 | AM-111 prevents hearing loss from semicircular canal injury in otitis media. Laryngoscope. 2010 Jan;120(1):178-82. doi: 10.1002/lary.20759. | ||||
Ref 528318 | J Med Chem. 2006 Jul 27;49(15):4455-8.Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 528524 | Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. | ||||
Ref 552744 | Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim Biophys Acta. 2008 Jan;1784(1):76-93. Epub 2007 Oct 11. |
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