title: Backbone cyclic peptide inhibitors of protein kinase B (PKB/Akt).
abstract: 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.
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Yftah
authors.initials: Y
authors.lastname: Tal-Gan
authors.forename: Mattan
authors.initials: M
authors.lastname: Hurevich
authors.forename: Shoshana
authors.initials: S
authors.lastname: Klein
authors.forename: Avraham
authors.initials: A
authors.lastname: Ben-Shimon
authors.forename: David
authors.initials: D
authors.lastname: Rosenthal
authors.forename: Carina
authors.initials: C
authors.lastname: Hazan
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Masha Y
authors.initials: MY
authors.lastname: Niv
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D001120:Arginine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D020134:Catalytic Domain; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000577:Amides; D019151:Peptide Library; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D014508:Urea; D001120:Arginine; D011392:Proline; D051057:Proto-Oncogene Proteins c-akt