Targeting ovarian cancer using fragment-based drug discovery

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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.