title: In vitro selection of anti-Akt2 thioether-macrocyclic peptides leading to isoform-selective inhibitors.
abstract: The Akt kinase family, consisting of three isoforms in humans, is a well-validated class of drug target. Through various screening campaigns in academics and pharmaceutical industries, several promising inhibitors have been developed to date. However, due to the mechanistic and structural similarities of Akt kinases, it is yet a challenging task to discover selective inhibitors against a specific Akt isoform. We here report Akt-selective and also Akt2 isoform-selective inhibitors based on a thioether-macrocyclic peptide scaffold. Several anti-Akt2 peptides have been selected from a library by means of an in vitro display system, referred to as the RaPID (Random nonstandard Peptide Integrated Discovery) system. Remarkably, the majority of these "binding-active" anti-Akt2 peptides turned out to be "inhibitory active", exhibiting IC(50) values of approximately 100 nM. Moreover, these peptides are not only selective to the Akt kinase family but also isoform-selective to Akt2. Particularly, one referred to as Pakti-L1 is able to discriminate Akt2 250- and 40-fold over Akt1 and Akt3, respectively. This proof-of-concept case study suggests that the RaPID system has a tremendous potential for the discovery of unique inhibitors with high family- and isoform-selectivity.
authors.affiliation: Department of Chemistry, Graduate School of Science, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Jumpei
authors.initials: J
authors.lastname: Morimoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
mesh_terms: D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D047028:Macrocyclic Compounds; D010455:Peptides; D047428:Protein Kinase Inhibitors; D013440:Sulfides; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt