Toward a PKB inhibitor: Modification of a selective PKA inhibitor by rational design

Hadas Reuveni, Nurit Livnah, Tamar Geiger, Shoshana Klein, Osnat Ohne, Ilana Cohen, Moran Benhar, Gary Gellerman, Alexander Levitzki

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


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.

Original languageEnglish
Pages (from-to)10304-10314
Number of pages11
Issue number32
StatePublished - 13 Aug 2002
Externally publishedYes


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