Targeting ovarian cancer using fragment-based drug discovery

高级别浆液性癌是最常见的卵巢癌类型，约占所有病例的三分之二和近80%的死亡。治疗依赖于使用铂剂，但耐药性出现，这可能是由基因CCNE 1的扩增驱动的。该基因的蛋白质产物（细胞周期蛋白E1）是一种细胞周期调节因子，可结合并激活激酶cdk 2以促进增殖。因此，细胞周期蛋白E1/cdk 2蛋白/蛋白相互作用（PPI）提供了一个迫切需要的靶向治疗的机会。该项目将利用我们的共价筛选平台（qIT，Angew Chem Int艾德英格兰出版社（Angl.（2018）57：5257-5261）。该项目将是生物化学，生物物理学，结构生物学，合成和药物化学的混合。学生将开发新的技术来连接和显示化学片段进行筛选，然后识别，鉴定和开发命中片段作为细胞周期蛋白E1活性的调节剂。这些化合物将在已建立的卵巢癌细胞系中进行测试，这些细胞系对铂类药物具有和不具有获得性耐药性。

High-grade serous carcinoma is the commonest type of ovarian cancer and accounts for approximately two-thirds of all cases and nearly 80% of deaths. Treatment relies on the use of platinum agents but resistance arises, which can be driven by amplification of the gene CCNE1. The protein product of this gene (cyclin E1) is a cell cycle regulator that binds to and activates the kinase cdk2 to promote proliferation. Thus, the cyclin E1/cdk2 protein/protein interaction (PPI) offers an opportunity for an urgently required targeted therapy. This project will define novel chemical entities to regulate this interaction, exploiting our covalent screening platform (qIT, Angew Chem Int Ed Engl. (2018) 57:5257-5261). The project will be a mix of biochemistry, biophysics, structural biology, synthetic and medicinal chemistry. The student will develop new technology to attach and display chemical fragments for screening, then identify, characterise and develop hit fragments to be regulators of cyclin E1 activity. These compounds will then be tested in established ovarian cancer cell lines with and without acquired resistance to platinum agents.