Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00132
Target NameRAC-alpha serine/threonine kinase    
Type of TargetClinical trial target    
Drug Potency against TargetRX-0201IC50 = 100 nM[1]
CI-1033IC50 = 19 nM[2]
CI-1033IC50 = 19 nM[3]
XL418IC50 = 20 nM[4]
EnzastaurinIC50 = 30 nM[5]
MK-2206IC50 = 8~65 nM[6]
A-443654;A-4436554IC50 = 0.16 nM[7]
BX-517IC50 = 100 nM[8]
4,5,6-trihydroxy-3-methylphthalideIC50 = 19700 nM[9]
SB-747651AIC50 = 200 nM[10]
BMS-754807IC50 = 22 nM[11]
(Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-oneIC50 = 3000 nM[8]
GSK-690693Ki = 1 nM[10]
Action against Disease ModelPerifosinePerifosine showed single agent anti-proliferative activity in a variety of gastric cancer cell lines. In 8/13 cell lines resistant to 5-FU, perifosine showed a synergistic antiproliferative activity with 5-FU. In 72% of cell lines, high basal levels of pAkt were detected. Treatment with perifosine reduced t uMor growth in nude mice inoculated subcutaneously with the YCC 2 gastric cancer cell line. The Akt inhibitor Perifosine strongly enhances the antit uMor and antivascular activity of CD34+ cells engineered to express membrane-bound TRAIL[12]
The Effect of Target Knockout, Knockdown or Genetic VariationsPhenotype:Growth retardation; perinatal lethality; shorter life span when subjected to genotypic stress; osteopenia; Phenotype:Diabetes mellitus-like syndrome; insulin-resistant diabetes; growth deficiency; Phenotype:Small brain; mildneurologic defects; Phenotype:Perinatal lethality; severe musculoskeletal and adipose tissue defects; Phenotype:Embryonically lethal (E10.5); cardiovascular and nervous system defects; Phenotype:viable and fertile; Phenotype:Bigger heart; Phenotype:Increased T-cell survival; Phenotype:beta-cell hypertrophy, hyperplasia and hyperinsulinemia; Phenotype:Delay in mammary gland involution; enhanced t uMor progression; Phenotype:intraepithelial neoplasia[13]
Ref 1Use of antisense oligonucleotides to inhibit the expression of human Akt-1. (United States Patent 7122527 ) To Reference
Ref 2Selleck Chemicals LLC. Company report from Selleck To Reference
Ref 3Company report from Selleck To Reference
Ref 4Discovery of novel anticancer therapeutics targeting the PI3K/Akt To Reference
Ref 5Curr Top Med Chem. 2009;9(7):640-54.Small molecule inhibitors of PKCTheta as potential antiinflammatory therapeutics. To Reference
Ref 6Curr Top Med Chem. 2010;10(4):458-77.The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update. To Reference
Ref 7J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25.Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. To Reference
Ref 8Bioorg Med Chem Lett. 2007 Jul 15;17(14):3814-8. Epub 2007 Apr 27.Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity. To Reference
Ref 9J Nat Prod. 2004 Dec;67(12):2086-9.A phthalide with in vitro growth inhibitory activity from an oidiodendron strain. To Reference
Ref 10J Med Chem. 2008 Sep 25;51(18):5663-79.Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. To Reference
Ref 11J Med Chem. 2009 Dec 10;52(23):7360-3.Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. To Reference
Ref 12J Pharmacol Exp Ther. 1999 Mar;288(3):1117-24.Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. To Reference
Ref 13EMBO J. 2000 Jun 1;19(11):2537-48.The conserved phosphoinositide 3-kinase pathway determines heart size in mice. To Reference



 

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