Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer (expression). Homo sapiens

Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. The most prevalent consensus peptide series matched the tumor suppressor Deleted in Liver Cancer 1 (DLC1). ERG inhibitory peptides and derived peptidomimetics (EIPs) bound with high affinity and specificity leading to proteolytic degradation of ERG. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other cancers. Overall design: ERG genes in VCaP cell were knocked down by siERG or siControls for 48 hrs. Biological replicates: 2 control replicates, 2 experimental replicates. ERG proteins were destablized by RI-EIP1 or RI-muEIP1 for 72 hours. Biological replicates: 2 control replicates, 2 experimental replicates.