title: Toward a PKB inhibitor: modification of a selective PKA inhibitor by rational design.
abstract: Protein kinase B/Akt (PKB) is an anti-apoptotic protein kinase that has strongly elevated activity in human malignancies. We therefore initiated a program to develop PKB inhibitors, "Aktstatins". We screened about 500 compounds for PKB inhibitors, using a radioactive assay and an ELISA assay that we established for this purpose. These compounds were produced as combinatorial libraries, designed using the structure of the selective PKA inhibitor H-89 as a starting point. We have identified a successful lead compound, which inhibits PKB activity in vitro and in cells overexpressing active PKB. The new compound shows reversed selectivity to H-89: In contrast to H-89, which inhibits PKA 70 times better than PKB, the new compound, NL-71-101, inhibits PKB 2.4-fold better than PKA. The new compound, but not H-89, induces apoptosis in tumor cells in which PKB is amplified. We have identified structural features in NL-71-101 that are significant for the specificity and that can be used for future development and optimization of PKB inhibitors.
authors.affiliation: Department of Biological Chemistry, The Silverman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel, and Peptor Ltd., Rehovot, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Reuveni
authors.forename: Nurit
authors.initials: N
authors.lastname: Livnah
authors.forename: Tamar
authors.initials: T
authors.lastname: Geiger
authors.forename: Shoshana
authors.initials: S
authors.lastname: Klein
authors.forename: Osnat
authors.initials: O
authors.lastname: Ohne
authors.forename: Ilana
authors.initials: I
authors.lastname: Cohen
authors.forename: Moran
authors.initials: M
authors.lastname: Benhar
authors.forename: Gary
authors.initials: G
authors.lastname: Gellerman
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; C464603:NL-71-101; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D000255:Adenosine Triphosphate; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide