ICF: Novel smant of CCNE1-amplll molecule inhibitors for the treatmeified cancers

This project aims to take important steps towards developing a drug that will target the Achilles' heel of the cancerous cells found in 1 in 5 patients diagnosed with high grade serous ovarian cancer. Patients with this form of cancer currently have a very poor prognosis, and undergo harsh chemotherapy that provides limited benefits in terms of quality or duration of life. The vulnerability of the ovarian cancer in these patients arises from the fact that these particular cancer cells have multiple copies of the gene that encodes cyclin E. This results in cyclin E protein being produced at abnormally high levels and as a consequence the cells become addicted to cyclin E for their ability to further divide and survive. Our structural studies have provided novel insights into how aberrant cyclin E signaling may be prevented with a small molecule inhibitor, which would be selectively toxic to ovarian cancers that are dependent upon this pathway for survival. The project team has extensive expertise in drug discovery and has established the experimental systems needed to develop such inhibitors, with chemical start points being identified. The team has also formed collaborations with clinical experts who specialise in the treatment of aggressive ovarian cancers. Clinicians would be able to easily identify the patients with elevated cyclin E who would benefit from a drug developed for these tumour cells; an example of a personalised medicine. By the end of the project, the team aims to have developed the inhibitors to a point where they can demonstrate selective effects on ovarian cancer cells with elevated cyclin E levels. This would position the project for further development involving the final optimisation of inhibitors towards a drug that could be developed for clinical use.