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

开发用作抗肿瘤剂的组织蛋白酶 V 抑制剂。

• 批准号: MR/Y503447/1
• 负责人: Roberta Burden
• 金额: $ 29.62万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY503447%2F1
• 关键词: Development; Cathepsin; inhibitor; application; anti

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.

尽管过去 25 年生存率有所提高，但诊断为雌激素受体阳性 (ER+) 乳腺癌的女性中，有五分之一将死于该病。 ER+肿瘤通常对内分泌（激素）治疗反应良好，但许多肿瘤随后对这些标准治疗产生耐药性，导致疾病复发、转移和死亡。复发性、耐药性和转移性 ER+ 乳腺癌的替代治疗选择受到严重限制，这凸显了为这些患者开发改进的治疗策略的主要未满足的临床需求。该提案的主要目的是开发一种针对半胱氨酸蛋白酶组织蛋白酶 V 的小分子抑制剂（ CTSV），我们已将其确定为 ER+ 乳腺癌的新治疗靶点。 CTSV因其在生理条件（睾丸和胸腺）下的限制表达和特定的病理功能而成为有吸引力的治疗靶点。原发性乳腺肿瘤中 CTSV 表达升高与远处转移和疾病复发相关，而浸润前乳腺导管原位癌 (DCIS) 组织中 CTSV 表达升高与侵袭性疾病的进展相关。我们实验室的研究重点是剖析 CTSV 在 ER+ 乳腺癌中的作用。我们发现 CTSV 表达升高与 ER+ 乳腺癌的不良预后相关，它会促进肿瘤细胞增殖和侵袭。我们还发现 CTSV 驱动 GATA3 降解并提高细胞外 ATP 水平 (eATP)，这两者都会促进乳腺癌转移。在我们的实验室之外，研究表明 CTSV 蛋白水解活性对于抑制免疫细胞的细胞毒性至关重要，因此 CTSV 抑制剂可以通过增强免疫细胞的细胞毒性来作为肿瘤细胞免疫治疗方法。总的来说，这项研究支持进一步检查 CTSV 作为乳腺癌治疗靶点是有必要的。为了实现这一目标，我们必须开发一种抑制 CTSV 蛋白水解活性的化合物。我们已经鉴定出一种对 CTSV 具有效力和选择性的小分子抑制剂，该项目将专注于该分子的细化和改进。我们将使用结构-活性关系 (SAR) 合成方法来确定我们生成的抑制剂的化学结构与通过选择性抑制 CTSV 对生物活性产生的影响之间的关系。先导化合物将在一系列基于细胞的测定中进行验证，以确定最有效和选择性的命中化合物的功能。