akt-i-1-2-compound and Prostatic-Neoplasms

akt-i-1-2-compound has been researched along with Prostatic-Neoplasms* in 2 studies

Other Studies

2 other study(ies) available for akt-i-1-2-compound and Prostatic-Neoplasms

ArticleYear
Rapid assembly of diverse and potent allosteric Akt inhibitors.
    Bioorganic & medicinal chemistry letters, 2008, Mar-15, Volume: 18, Issue:6

    This paper describes the rapid assembly of four different classes of potent Akt inhibitors from a common intermediate. Among them, a pyridopyrimidine series displayed the best intrinsic and cell potency against Akt1 and Akt2. This series also showed a promising pharmacokinetic profile and excellent selectivity over other closely related kinases.

    Topics: Allosteric Site; Animals; Apoptosis; Caspases; Dogs; Female; Humans; Male; Metabolic Clearance Rate; Molecular Structure; Ovarian Neoplasms; Phosphorylation; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Structure-Activity Relationship; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured

2008
Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors.
    The Biochemical journal, 2005, Jan-15, Volume: 385, Issue:Pt 2

    We developed a high-throughput HTRF (homogeneous time-resolved fluorescence) assay for Akt kinase activity and screened approx. 270000 compounds for their ability to inhibit the three isoforms of Akt. Two Akt inhibitors were identified that exhibited isoenzyme specificity. The first compound (Akt-I-1) inhibited only Akt1 (IC50 4.6 microM) while the second compound (Akt-I-1,2) inhibited both Akt1 and Akt2 with IC50 values of 2.7 and 21 microM respectively. Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM. These compounds were reversible inhibitors, and exhibited a linear mixed-type inhibition against ATP and peptide substrate. In addition to inhibiting kinase activity of individual Akt isoforms, both inhibitors blocked the phosphorylation and activation of the corresponding Akt isoforms by PDK1 (phosphoinositide-dependent kinase 1). A model is proposed in which these inhibitors bind to a site formed only in the presence of the PH domain. Binding of the inhibitor is postulated to promote the formation of an inactive conformation. In support of this model, antibodies to the Akt PH domain or hinge region blocked the inhibition of Akt by Akt-I-1 and Akt-I-1,2. These inhibitors were found to be cell-active and to block phosphorylation of Akt at Thr308 and Ser473, reduce the levels of active Akt in cells, block the phosphorylation of known Akt substrates and promote TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in LNCap prostate cancer cells.

    Topics: 3-Phosphoinositide-Dependent Protein Kinases; Adenosine Triphosphate; Apoptosis Regulatory Proteins; Benzylamines; Binding, Competitive; Blood Proteins; Carcinoma; Caspases; Cell Line, Tumor; Cloning, Molecular; Enzyme Activation; Enzyme Inhibitors; Female; Heterocyclic Compounds, 2-Ring; Humans; Isoenzymes; Male; Membrane Glycoproteins; Molecular Structure; Peptides; Phosphoproteins; Phosphorylation; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Quinoxalines; Sequence Homology, Amino Acid; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha; Uterine Cervical Neoplasms

2005