Development of a Cathepsin V inhibitor for application as an anti-tumour agent.

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Despite improved survival rates over the last 25 years, 1 in 5 women diagnosed with Estrogen Receptor positive (ER+) breast cancer will die from their disease. ER+ tumours generally respond well to endocrine (hormone) therapy, however many tumours subsequently develop resistance to these standard treatments, resulting in disease recurrence, metastasis and death. Alternative treatment options for recurrent, resistant and metastatic ER+ breast cancer is severely limited, highlighting the major unmet clinical need to develop improved therapeutic strategies for these patients.The main aim of this proposal is to develop a small molecule inhibitor targeting cysteine protease Cathepsin V (CTSV), which we have identified as a novel therapeutic target in ER+ breast cancer. CTSV is an attractive therapeutic target due to its restricted expression under physiological conditions (testis and thymus) and specific pathological functions. Elevated CTSV expression in primary breast tumours has previously been correlated with the presence of distant metastasis and disease recurrence, while elevated CTSV expression in pre-invasive breast ductal carcinoma in situ (DCIS) tissue has been correlated with progression to invasive disease. Research within our laboratory has focused on dissecting the role of CTSV in ER+ breast cancer. We have discovered elevated expression of CTSV is associated with poor prognosis in ER+ breast cancer, where it promotes tumour cell proliferation and invasion. We have also identified that CTSV drives GATA3 degradation and enhances extracellular ATP levels (eATP), both of which promote breast cancer metastasis. Beyond our laboratory, research has illustrated that CTSV proteolytic activity is crucial in suppressing immune cell cytotoxicity, therefore CTSV inhibitors could have utility as a tumour cell immunotherapy approach by enhancing immune cell cytotoxicity. Collectively, this research supports that further examination of CTSV as a therapeutic target in breast cancer is warranted. To achieve this, it is imperative that we develop a compound that inhibits CTSV proteolytic activity. We have identified a small molecule inhibitor that exhibits potency and selectivity towards CTSV, and this project will focus on the refinement and improvement of this molecule. We will use a structure-activity relationship (SAR) synthesis approach to determine the relationship between the chemical structure of the inhibitors we generate and the resultant impact on biological activity through selective inhibition of CTSV. Lead compounds will be validated in a series of cell-based assays to determine the functionality of the most potent and selective hit compounds.