Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00102
Target NameMitogen-activated protein kinase 8    
Type of TargetClinical trial target    
Drug Potency against TargetAM-111IC50 < 500 nM[1]
CC-401IC50 = 10000 nM[2]
SP-600125IC50 = 110 nM[3]
2-(2-(pentyloxy)pyrimidin-4-ylamino)benzoic acidIC50 = 1100 nM[4]
NM-PP1IC50 = 140 nM[5]
2-(2-butoxypyrimidin-4-ylamino)benzoic acidIC50 = 1900 nM[4]
N-(4-amino-6-butoxy-5-cyanopyridin-2-yl)acetamideIC50 = 2100 nM[6]
2-(2-propoxypyrimidin-4-ylamino)benzoic acidIC50 = 2300 nM[4]
2-(2-(butylamino)pyrimidin-4-ylamino)benzoic acidIC50 = 2600 nM[4]
AS-601245IC50 = 2600 nM[5]
2-(2-phenoxypyrimidin-4-ylamino)benzoic acidIC50 = 300 nM[4]
2-(2-(phenylamino)pyrimidin-4-ylamino)benzamideIC50 = 590 nM[4]
2-(2-sec-butoxypyrimidin-4-ylamino)benzoic acidIC50 = 700 nM[4]
N-(6-ethoxypyridin-2-yl)acetamideIC50 = 750 nM[6]
N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)acetamideIC50 = 840 nM[7]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamideKi = 1900 nM[6]
Action against Disease ModelAM-111AM-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 in the 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.[8]
The Effect of Target Knockout, Knockdown or Genetic VariationsCombined 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 that in 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.[9]
Ref 1Biochim Biophys Acta. 2010 Mar;1804(3):463-75. Epub 2009 Nov 10.c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. To Reference
Ref 2Biochim Biophys Acta. 2008 Jan;1784(1):76-93. Epub 2007 Oct 11.Inhibitors of c-Jun N-terminal kinases: JuNK no more? To Reference
Ref 3Bioorg Med Chem. 2008 Apr 15;16(8):4715-32. Epub 2008 Feb 13.Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1). To Reference
Ref 4Bioorg 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. To Reference
Ref 5Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. To Reference
Ref 6J 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. To Reference
Ref 7J 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. To Reference
Ref 8Laryngoscope. 2010 Jan;120(1):178-82.AM-111 prevents hearing loss from semicircular canal injury in otitis media. To Reference
Ref 9Diabetologia. 2008 Aug;51(8):1493-504. Epub 2008 Jun 5.Silencing Jnk1 and Jnk2 accelerates basal lipolysis and promotes fatty acid re-esterification in mouse adipocytes. To Reference



 

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