Ovarian clear cell carcinoma (CCC) is a rare subtype of ovarian cancer accounting for 5-10% of ovarian cancer cases. CCCs are resistant to platinum-based chemotherapy and the development of targeted therapeutics for this disease are of high priority. Transcription factor HNF1β is overexpressed in CCC. A drop in proliferation was observed in CCC lines upon shRNA knockdown of HNF1β. We have demonstrated that the 229KKMRRNR235 peptide sequence in HNF1β is essential for nuclear import of the protein by generating HNF1β deletion mutants. Importin-α1 has been confirmed as the major nuclear import protein by GST pull-down experiments and nuclear import occurs via the major site on Importin-α. Targeting protein-protein interactions that are based on unstructured proteins are a major challenge and we chose to address this by developing a peptide-based inhibitor. We are currently developing stapled peptides of the flexible loop region 229KKMRRNR235 using Fmoc-solid phase peptide synthesis and copper click chemistry to target the Importin-α - HNF1β protein-protein interaction competitively.

Targeting transcription factor HNF1β in ovarian cancer using stapled peptides

251st National Meeting (2016)

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