Abstract
Abstract An approach to drugging ‘undruggable’ target proteins using macrocyclic, epitope targeted peptide based affinity reagents is demonstrated. An unbiased comprehensive Cu-catalyzed Azide Alkyne Cycloaddition cyclized peptide macrocyclic library is synthesized and screened against the phoshoS474 containing 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 phospho-S474 region of Akt, inhibits the Akt kinase in in vitro kinase assays. This ligand is being optimized, through systematic changes in its composition, to increase its cell permeability characteristics, so that its effects can be studied in Akt overexpressing carcinoma cell lines. The optimized macrocyclic peptide can eventually be used as an in vivo imaging probe and as a peptide inhibitor drug. Citation Format: Arundhati Nag. Circle Akt in: Epitope catalyzed assembly of macrocyclic therapeutics against phosphorylated Akt. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2172.
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