Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer.

Mareike M Wiedmann,David R Spring,Wenshu Xu,Hannah F Sore,Yuteng Wu,James D Brenton,Laura Itzhaki,Murray Stewart,Yaw Sing Tan,Chandra S Verma,Shintaro Aibara

doi:10.1002/anie.201609427

Abstract

There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum‐based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA‐mediated knockdown of the target protein, HNF1β, in five high‐ and low‐HNF1β‐expressing CCC lines. To inhibit the protein function, cell‐permeable, non‐helical constrained proteomimetics to target the HNF1β–importin α protein–protein interaction were designed, guided by X‐ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors.

Highlights

There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy
The transcription factor hepatocyte nuclear factor 1b (HNF1b) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through small hairpin RNA (shRNA)-mediated knockdown of the target protein, HNF1b, in five high- and low-HNF1bexpressing CCC lines
We have recently confirmed the existence of a nuclear localization signal (NLS) within the DNA-binding domain (DBD) of HNF1b,[6] which directs the nuclear import of the protein.[7]