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.

尽管在过去的25年里存活率有所提高，但被诊断为雌激素受体阳性(ER+)乳腺癌的女性中，有1/5会死于她们的疾病。ER+肿瘤一般对内分泌(激素)治疗反应良好，但许多肿瘤随后对这些标准治疗产生抗药性，导致疾病复发、转移和死亡。复发、耐药和转移性ER+乳腺癌的替代治疗方案严重有限，凸显了临床上尚未满足的主要需求，即为这些患者开发改进的治疗策略。本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V(CTSV)的小分子抑制剂，我们已将其确定为ER+乳腺癌的新治疗靶点。CTSV在生理条件下(睾丸和胸腺)的表达受限，具有特殊的病理功能，是一种有吸引力的治疗靶点。CTSV在原发乳腺肿瘤中的高表达与远处转移和疾病复发相关，而在浸润性乳腺导管原位癌(DCIS)组织中CTSV的高表达与浸润性疾病的进展相关。我们实验室内的研究主要集中在剖析CTSV在ER+乳腺癌中的作用。我们发现，在ER+乳腺癌中，CTSV的高表达与预后不良有关，它促进了肿瘤细胞的增殖和侵袭。我们还发现，CTSV驱动GATA3的降解并提高细胞外ATP水平(EATP)，这两者都促进了乳腺癌的转移。除了我们的实验室外，研究表明CTSV的蛋白水解性在抑制免疫细胞细胞毒性方面是至关重要的，因此CTSV抑制剂可能通过增强免疫细胞细胞毒性而作为一种肿瘤细胞免疫治疗方法。总而言之，这项研究支持进一步研究CTSV作为乳腺癌治疗靶点的必要性。为了实现这一点，我们必须开发一种抑制CTSV蛋白水解酶活性的化合物。我们已经确定了一种对CTSV具有高效和选择性的小分子抑制剂，本项目将专注于该分子的提纯和改进。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而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分析中得到验证，以确定最有效和最有选择性的Hit化合物的功能。