Authors:
MM Wiedmann, YS Tan, Y Wu, S Aibara, W Xu, HF Sore, CS Verma, L Itzhaki, M Stewart, JD Brenton, DR Spring
Journal name: 
Angew Chem Int Ed Engl
Citation info: 
56(2):524-529
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.
DOI: 
http://doi.org/10.1002/anie.201609427
Research group: 
Brenton Group
E-pub date: 
09 Jan 2017