1. Discovery of trans-3,4'-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation
- Author
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Vincent L. Giranda, Tilman Oltersdorf, Vincent S. Stoll, Shannon S Arries, Eric F. Johnson, Xuesong Liu, Yan Luo, Kennan C. Marsh, Jianchun Gong, Vered Klinghofer, Jennifer J. Bouska, Yan Shi, Qun Li, Chris Dalton, Ron De Jong, Clarissa G. Jakob, Akiyo Claibone, Saul H. Rosenberg, Tongmei Li, Joy Bauch, and Gui-Dong Zhu
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,AKT1 ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,Biochemistry ,Glycogen Synthase Kinase 3 ,Structure-Activity Relationship ,Adenosine Triphosphate ,Neoplasms ,Drug Discovery ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Protein kinase A ,Molecular Biology ,Protein kinase B ,CAMK ,Cell Proliferation ,Binding Sites ,Kinase ,Chemistry ,Organic Chemistry ,Ethylenes ,Protein-Tyrosine Kinases ,Calcium-Calmodulin-Dependent Protein Kinases ,Molecular Medicine ,Signal transduction ,Tyrosine kinase ,Proto-Oncogene Proteins c-akt - Abstract
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4′-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC50 values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
- Published
- 2005