Oncogenic inhibition of the p53 tumour suppressor is a key feature of human cancer. However, relatively few oncogenic drug targets which inhibit p53 have been identified using a variety of model systems. As a prototype, a clinical proteomics screen was initiated in preneoplastic disease where selection pressures were placed on p53 gene mutation to identify clinically relevant and novel p53 inhibitors. This screen identified a protein named Anterior Gradient-2 (AGR2) as a novel type of p53 inhibitor. As reactivation of p53 holds promise as a therapeutic strategy for cancer treatment, AGR2 still requires validation as an anti-cancer drug target. Many signalling proteins function by binding to linear domains and combinatorial peptide libraries facilitate lead identification for validating a potential drug target. The AGR2 protein localized in the endoplasmic reticulum and nuclear compartments and this distribution was mediated by a Cterminal KTEL sequence. The transfection of AGR2 into cells stimulated p53 protein accumulation in the cytosol forming a novel assay for measuring AGR2-mediated inhibition of p53. Optimized AGR2-binding penta-peptide aptamers were minimized using substitution mutagenesis. Transfection of EGFP-peptide-aptamers containing the core TxIYY pentapeptide sequence stabilized p53 and increased its nuclear localization. The fusion of the TxIYY penta-peptide to the cell membrane permeable antennapedia peptide also resulted in a similar nuclear relocalization of p53 protein. These data indicate that the AGR2 pathway can be targeted with peptide-aptamers resulting in p53 stabilization and highlight the utility of linking clinical proteomics to combinatorial peptide chemistry to rapidly discover and validate uncharacterized proteins as potential anti-cancer drug targets.