The epidermal growth factor receptor (EGFR) is overexpressed in multiple carcinomas and is the focus of a variety of targeted therapies. Here we report the design of peptide-based compounds that mimic the EGFR dimerization arm and inhibit allosteric activation of EGFR. These peptides are modified to contain a triazolyl bridge between the peptide strands to constrain the EGFR dimerization arm β-loop. In this study, we demonstrate that these peptides have significantly improved proteolytic stability over the non-modified peptide sequence, and their inhibitory effects are dependent on the number of the methylene units and orientation of the introduced triazolyl bridge. We identified a peptide, EDA2, which downregulates receptor phosphorylation and dimerization and reduces cell viability. This is the first example of a biologically active triazolyl-bridged peptide targeting the EGFR dimerization interface that effectively downregulates EGFR activation.
The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this β-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable β-loop peptides for disruption of protein-protein interactions.
A Kinase Interating Protein 1 (AKIP1) is highly upregulated in prostate cancer and can mislocalize Protein Kinase A (PKA) by translocating it from the cytoplasm to the nucleus. Further, AKIP1 acts as a scaffold to stabilize interactions between PKA and other proteins, thereby influencing PKA‐mediated signaling. PKA also plays an important role in late‐stage, androgen‐independent prostate cancer by promoting androgen‐dependent transcription and nuclear localization of the androgen receptor. While it is apparent that AKIP1 plays an important regulatory role for PKA, the specific changes that are mediated by AKIP1 in prostate cancer remain largely unknown. Therefore, it is of great importance to understand the biological implications of nuclear PKA activity and how this relates to androgen receptor localization and signaling in late‐stage prostate cancer. To address this, we have developed novel peptide‐based chemical biology tools that act to disrupt protein‐protein interactions as a means to interrogate AKIP1 activity in the context of prostate cancer cells. By applying these chemically stabilized compounds, we can elegantly and selectively disrupt interactions between PKA and AKIP1 while leaving the catalytic activity of PKA intact, thereby enabling us to interrogate the role of AKIP1 in prostate cancer as well as uncover its regulatory role on androgen receptor signaling.
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