Development of inhibitors for CUX1 and PARG, two novel therapeutic targets for hard-to-treat breast cancers

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Challenge: Triple-negative breast cancer (TNBC) accounts for 15 to 20 % of all breast cancer patients, but for about 25 % of all breast cancer deaths. There is currently no targeted treatment for TNBC, while only about 30 % of TNBCs are sensitive to conventional therapies. In addition, no more than 50 % of HER2-positive (HER2+) breast cancer patients respond to targeted therapy. Patients are currently treated using conventional therapies, but remission is usually short and relapses frequently. There is, therefore, an urgent need for new therapies for these types of breast cancer.

Solution: The research team had previously identified and validated two novel and “druggable” therapeutic targets, namely CUX1 and PARG, that are important key regulators of DNA repair mechanisms. This project, in partnership with the NEOMED Institute, aimed to identify new CUX1 and PARG inhibitors using a medicinal chemistry approach which first used high-throughput screening and validation assays. After optimizing the high-throughput screening assay, the team identified a few potentially interesting inhibitors of PARG, as well as compounds that inhibit functional domains of CUX1. However, the project had to be stopped prematurely because the inhibitors did not meet the partners’ requirements.

Achievements/Impact: The academic research team has strengthened its expertise in high-throughput screening and in vitro assays when trying to identify functional inhibitors of difficult-to-treat breast cancer cell regulators. The team continues to work towards the development of new candidate inhibitors.

Principal Investigator:
Alain Nepveu
McGill University
Co-investigators
Michael Witcher
Jewish General Hospital
Kemal Payza
NEOMED Institute
Stopped Project
$ 813,019 / 1 year
Supported by CQDM through:
– MEI
And by co-funding partners:
– Canadian Cancer Society (CCS)
– NEOMED Institute
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