Use of iterative in situ click chemistry to develop a capture agent specific for a transforming point mutation in the pleckstrin homology domain of Akt1

Abstract

We present an iterative in situ click chemistry approach to sequentially assemble peptide ligands that can selectively bind to and inhibit a transforming point mutation (E17K) found in the Pleckstrin Homology Domain (PHD) of the Akt1 kinase. The Akt1 kinase plays a critical role in the PI3K signaling pathway - the activation of which is closely linked to tumor development and cancer cell survival. It has recently been shown that the E17K mutation in the PHD of Akt1 results in an increased affinity of the PHD for the PIP3 substrate. Consequently, deregulated recruitment of Akt1 to the cell membrane causes constitutive activation of the PI3K pathway, which has been shown to induce leukemia in mice