Backbone cyclic peptide inhibitors of protein kinase B (PKB/Akt)

Yftah Tal-Gan, Mattan Hurevich, Shoshana Klein, Avraham Ben-Shimon, David Rosenthal, Carina Hazan, Deborah E. Shalev, Masha Y. Niv, Alexander Levitzki, Chaim Gilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Elevated levels of activated protein kinase B (PKB/Akt) have been detected in many types of cancer. Substrate-based peptide inhibitors have the advantage of selectivity due to their extensive interactions with the kinase-specific substrate binding site but often lack necessary pharmacological properties. Chemical modifications of potent peptide inhibitors, such as cyclization, may overcome these drawbacks while maintaining potency. We present an extensive structure-activity relationship (SAR) study of a potent peptide-based PKB/Akt inhibitor. Two backbone cyclic (BC) peptide libraries with varying modes of cyclization, bridge chemistry, and ring size were synthesized and evaluated for in vitro PKB/Akt inhibition. Backbone-to-backbone urea BC peptides were more potent than N-terminus-to-backbone amide BC peptides. Several analogues were up to 10-fold more active than the parent linear peptide. Some activity trends could be rationalized using computational surface mapping of the PKB/Akt kinase catalytic domain. The novel molecules have enhanced pharmacological properties which make them promising lead candidates.

Original languageAmerican English
Pages (from-to)5154-5464
Number of pages311
JournalJournal of Medicinal Chemistry
Issue number14
StatePublished - 28 Jul 2011


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