Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
Angew Chem Int Ed Engl. 2017 Jan 9;56(2):524-529. doi: 10.1002/anie.201609427. Epub 2016 Dec 5.
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.
目前针对卵巢透明细胞癌（CCC）的治疗选择有限，而且该癌症通常对铂类化疗药物有耐药性。因此，迫切需要新的治疗方法。转录因子肝细胞核因子 1β（HNF1β）在 CCC 中广泛过表达，被视为有吸引力的治疗靶点。这通过在 5 种高表达和低表达 HNF1β的 CCC 细胞系中，使用 shRNA 介导的靶向蛋白 HNF1β敲低得到了验证。为了抑制该蛋白的功能，根据 X 射线晶体学数据和分子动力学模拟，设计了针对 HNF1β-importinα 蛋白-蛋白相互作用的细胞穿透非螺旋约束蛋白模拟物。通过这种方式，我们开发了第一批报道的约束肽核输入抑制剂系列。重要的是，这种通用方法可以扩展到其他转录因子。
