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，占死亡人数的近80%。治疗依赖于铂类药物的使用，但由于CCNE1基因的扩增，会产生耐药性。该基因的蛋白产物（细胞周期蛋白E1）是一种细胞周期调节剂，结合并激活激酶cdk2以促进增殖。因此，周期蛋白E1/cdk2蛋白/蛋白相互作用（PPI）为迫切需要的靶向治疗提供了机会。该项目将定义新的化学实体来调节这种相互作用，利用我们的共价筛选平台（qIT, angnew Chem Int Ed english）。(2018) 57:5257 - 5261)。该项目将结合生物化学、生物物理学、结构生物学、合成化学和药物化学。该学生将开发新的技术来连接和显示用于筛选的化学片段，然后识别、表征和开发被击中的片段，以调节细胞周期蛋白E1的活性。然后，这些化合物将在已建立的卵巢癌细胞系中进行测试，无论是否对铂类药物产生获得性耐药性。

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.