Circle Akt In: Macrocycles against phosphorylated Akt

Abstract

An approach to targeting traditionally 'undruggable' target proteins using macrocyclic peptide based affinity reagent is demonstrated. An unbiased comprehensive Cu-catalyzed Azide Alkyne Cycloaddn. cyclized peptide macrocyclic library is synthesized and screened against the phoshoS474 contg. Hydrophobic Motif (HM) peptide epitope of Akt2. The best macrocyclic ligand, which exhibits specificity at the peptide and protein levels, is further extended through an in situ click screen to yield bivalent macrocyclic reagent with high affinity and specificity. The bivalent peptide, targeted against the phosphor-S474 region of Akt2, inhibits the Akt2 kinase in vitro. This ligand is being optimized, through medicinal chem. iterations, to improve its in vivo characteristics, so that its effects can be studied in relevant carcinoma cell lines. The optimized macrocyclic peptide can eventually be used as an in vivo imaging probe.