Chemical Approaches for Activity-Based Proteomics

基于活性的蛋白质组学的化学方法

• 批准号: 9021605
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 29.48万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021605
• 关键词: Achievement; Antineoplastic Agents; Apoptosis; Biochemical Pathway; Biological Markers; Biology; Caspase; Cell Survival; Chemicals; Couples; Cysteine; Development; Diagnosis; Disease; Drug Targeting; Enzymes; Ethers; Feedback; Genome; Goals; Grant; Growth; Health; Human; Hydrolase; Lipids; Lysine; Malignant Neoplasms; Maps; Metabolic Pathway; Mind; Modification; Molecular; Monitor; Output; Oxidative Stress; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Production; Proteins; Proteomics; Resistance; Role; Signal Pathway; Technology; Testing; Therapeutic; Tumor Markers; activity-based protein profiling; base; biological systems; cancer cell; cancer therapy; chemoproteomics; glucose uptake; human disease; innovation; kinase inhibitor; novel; oxidation; protein function; protein profiling; response; therapeutic target; tumor growth; tumorigenesis; tumorigenic

The ability to characterize entire classes of proteins based on activity would greatly accelerate both the assignment of protein function in the genome era and the identification of new biomarl<ers and therapeutic targets for the diagnosis and treatment of human disease. With this goal in mind, we have created innovative chemoproteomic platforms to profile protein activities en masse in native biological systems. In the past grant period, we advanced and applied these platforms and the following major achievements were attained: 1) discovery and inhibition of deregulated, pro-tumorigenic lipid hydrolases; 2) development of an integrated proteomic platform to discover novel forms of caspase-kinase crosstalk that regulate cancer apoptosis; 3) discovery of a novel post-translational modification that couples glucose uptake to glycolytic remodeling and the production of pro-tumorigenic metabolites; 4) development of a tag-free activity-based protein profiling (ABPP) platform to quantify and functionally characterize reactive cysteines in cancer; and 5) advancement of tag-free ABPP to optimize the activity and selectivity covalent kinase inhibitors as anti-cancer drugs. In this renewal application, we will build upon our past achievements to test the following major hypotheses of high significance to cancer and chemical biology: 1) lipid hydrolases form key bridges between metabolic and signaling pathways that promote tumorigenesis; 2) crosstalk between proteolytic and phosphorylation pathways regulate cancer cell survival and create tumor-specific biomarkers for monitoring cancer therapy and resistance; 3) 3-phosphoglyceryl-lysine (pgK) modifications constitute an intrinsic feedback pathway to remodel glycolytic output and stimulate tumor growth; 4) electrophile/oxidation-sensitive cysteines regulate cancer cell survival in response to oxidative stress; and 5) covalent kinase inhibitors optimized by tag-free ABPP will show enhanced on-target activity and reduced off-target interactions, thereby expanding their therapeutic window as anti-cancer drugs. The ultimate goal ofthis application is to Identify key biochemical pathways that support human cancer growth and malignancy. The molecular components of these pathways may represent new biomarkers and drug targets for cancer.

基于活性来表征整个蛋白质类别的能力将大大加速蛋白质的生物学特性。 基因组时代蛋白质功能的分配和新的生物学和治疗学的鉴定 用于诊断和治疗人类疾病的靶点。为了实现这一目标，我们创造了创新的 化学蛋白质组学平台来分析天然生物系统中的蛋白质活性。在过去的格兰特 期间，我们对这些平台进行了推进和应用，取得了以下主要成果：1） 发现和抑制失调的促肿瘤脂质水解酶; 2）开发一种整合的 蛋白质组学平台，以发现调节癌症细胞凋亡的新型半胱天冬酶-激酶串扰; 3） 发现了一种新的翻译后修饰，将葡萄糖摄取与糖酵解重塑偶联， 促肿瘤代谢产物的产生; 4）开发无标签的基于活性的蛋白质谱 （ABPP）定量和功能性表征癌症中的反应性半胱氨酸的平台;和 的无标签ABPP，以优化活性和选择性共价激酶抑制剂作为抗癌药物。在 在这次更新申请中，我们将在我们过去的成就基础上测试以下主要假设： 对癌症和化学生物学具有重要意义：1）脂质水解酶在代谢之间形成关键桥梁 和促进肿瘤发生的信号通路; 2）蛋白水解和磷酸化之间的串扰 通路调节癌细胞存活并产生肿瘤特异性生物标志物用于监测癌症治疗 3）3-磷酸甘油基-赖氨酸（pgK）修饰构成了一个内在的反馈途径， 重塑糖酵解输出并刺激肿瘤生长; 4）亲电/氧化敏感性半胱氨酸调节 响应于氧化应激的癌细胞存活;和5）通过无标签优化的共价激酶抑制剂 ABPP将显示出增强的靶向活性和减少的脱靶相互作用，从而扩大它们的靶向活性。 作为抗癌药物的治疗窗口。该应用程序的最终目标是确定关键的生化 支持人类癌症生长和恶性肿瘤的途径。这些途径的分子组成部分 可能代表癌症的新生物标志物和药物靶点。