A Proteomic Strategy for Inhibiting Cancer-Associated Enzymes

癌症仍然是最常见和最危及生命的疾病之一，有效的治疗和治愈方法很少。转移性癌支持其运动和侵袭行为的特殊分子特性是复杂和模糊的。一种普遍接受的概念描述了水解酶，如蛋白酶和脂肪酶，作为转移性肿瘤侵袭性的关键介质。为了确定新的癌症相关水解酶，Cravatt及其同事开发了一种称为基于活性的蛋白质图谱(ABPP)的化学蛋白质组学策略，该策略利用活性位点定向探针直接在整个细胞、问题和流体蛋白质组中读出水解酶功能的变化。在以前的研究中，鉴定了多种酶的活性，包括几种丝氨酸蛋白酶和脂肪酶，它们在几种不同的肿瘤类型中有差异表达。这些酶的许多活性都是未知的蛋白质，可能代表着癌症和其他疾病的诊断和治疗的新靶点。这项建议的目标是发现这些新的癌症相关水解酶的有效和选择性的化学抑制剂，然后测试特定的抑制剂对癌细胞增殖/侵袭的影响。在这项应用中，我们将应用多学科方法，利用合成化学、功能蛋白质组学和细胞生物学技术。

Cancer remains one of the most prevalent and life-threatening diseases for which effective treatments and cures are rare. The molecular properties special to metastativ carcinomas that support their motile and invasive behavior are complex and ill-defined. One generally accepted notion depicts hydrolytic enzymes, such as proteases and lipases, as critical mediators of the aggressive properties of metastatic tumors. To identify novel cancer-associated hydrolases, Cravatt and coworkers have developed a chemical proteomic strategy referred to as activity-based protein profiling (ABPP) the utilizes active site-directed probes to readout changes in hydrolase function directly in whole cell, issue, and fluid proteomes. In previous reseach efforts, multiple enzyme activities were identified, including several serine proteases and lipases, that were differentially expressed in several different tumor types. Many of these enzyme activities are uncharacterized proteins that may represent new targets for the diagnosis and treatment of cancer and other diseases. The goal of this proposal is to discover potent and selective chemical inhibitors of these novel cancer-associated hydrolases and then test the effects of specific inhibitors on cancer cell proliferation/invasion. In this application, we will apply an multidisciplinary approach, utilizing synthetic chemistry, functional proteomic, and cell biology techniques.