In Vitro Selection of Anti-Akt2 Thioether-Macrocyclic Peptides Leading to Isoform-Selective Inhibitors

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 have report Akt-selective and also Akt2 isoform-selective inhibitors based on 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 nonstranded peptide Integrated Discovery) system. Remarkable, the majority of these binding active anti-Akt2 peptide turned out to be inhibitory active, exhibiting IC50 values of approximately 100 nm. Moreover, these peptides are not selective to the Akt kinase family but also isoform-selective to Akt2. Particularly, one referred to as Pakti-L1 is able to discriminate Akt2 and Akt1 and Akt3, respectively. This proof-of-concept case study suggests that the RAPID system has a tremendous potential for the recovery for the discovery of unique inhibitors with high family- and isoform-selectively.