Rapid assembly of diverse and potent allosteric Akt inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 6, 2008, Pages 2211-2214

  Wu, Zhicai ^a   Robinson, Ronald G ^a   Fu, Sheng ^a   Barnett, Stanley F ^a   Defeo Jones, Deborah ^a   Jones, Raymond E ^a   Kral, Astrid M ^a   Huber, Hans E ^a   Kohl, Nancy E ^a   Hartman, George D ^a   Bilodeau, Mark T ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Akt inhibitor; Allosteric; Cancer; Kinase; Rapid assembly

Indexed keywords

CASPASE 3; PROTEIN AKT1; PROTEIN KINASE B; PROTEIN KINASE B BETA; PROTEIN KINASE B INHIBITOR; PYRIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ALLOSTERISM; ANIMAL EXPERIMENT; ARTICLE; DOG; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; ENZYME ACTIVITY; IC 50; NONHUMAN; STRUCTURE ACTIVITY RELATION;

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;

EID: 40749100180     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.10.023     Document Type: Article

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25. 50 represents biochemical inhibition of peptide phosphorylation with a full length of Akt enzyme. Detection was performed by homogeneous time resolved fluorescence (HTRF) using an europium chelate (Perkin-Elmer) [Eu(K)]-labeled phospho(S21)-GSK3α antibody (Cell Signaling Technologies) and streptavidin-linked XL665 fluorophore which binds to the biotin moiety on the substrate peptide (biotin-GGRARTSSFAEPG). For detail, see Ref. 6. Values are reported as single determinations or as the average of at least two determinations ± standard deviation.
26. Caspase assay measures the ability of Akt inhibitors to sensitize LNCaP cells to tumor necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis. As a surrogate for apoptosis induction we determine the enzymatic activity of the effector caspase 3 in compound-treated and untreated cells and values are reported as the fold induction. For details, see Ref. 7.
27. 50 represents the ability of inhibitors to block the phosphorylation of Akt isozymes in C33 A cells (human cervical carcinoma). For detail, see Ref. 7. Values are reported as single determinations or as the average of at least two determinations ± standard deviation.
28. Compound dosed 0.25 mpk iv as a solution in DMSO and the data are the average of two dogs.