Different active sites of the proteasome as drug targets in cancer

蛋白酶体的不同活性位点作为癌症药物靶点

• 批准号: 7629653
• 负责人: Alexei Kisselev
• 金额: $ 27.34万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-20 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629653
• 关键词: Active Sites; Address; Apoptosis; Apoptotic; Bortezomib; Breast Cancer Cell; Breast Cancer Model; Cancer cell line; Caspase; Catalytic Domain; Cell Line; Cell Proliferation; Cells; Clinical Treatment; Clinical Trials; Data; Development; Disease; Drug Delivery Systems; Epithelial Cells; Estrogen receptor negative; Figs - dietary; Goals; Growth; Human; Malignant Neoplasms; Mammary gland; Molecular; Molecular Target; Multiple Myeloma; Non-Malignant; Pathway interactions; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Property; Proteasome Inhibitor; Proteins; Public Health; Quality Control; Research Personnel; Resistance; Review Literature; Role; Site; Specificity; Staging; Structure; Testing; Therapeutic; Toxic effect; Trypsin; Ubiquitin; Velcade; Work; base; cancer cell; cancer therapy; cancer type; caspase-2; chymotrypsin; cytotoxic; cytotoxicity; design; inhibitor/antagonist; killings; malignant breast neoplasm; multicatalytic endopeptidase complex; neoplastic; novel; pre-clinical; programs; protein degradation; salinosporamide A; tumorigenesis

DESCRIPTION (provided by applicant): Protein degradation by proteasomes plays an essential role in the proliferation of malignant cells. The proteasome inhibitor VELCADE (bortezomib, PS-341) is being used for the treatment of multiple myeloma and is in clinical trials for the treatment of other cancers. The proteasome has three types of active sites: chymotrypsin-like (Beta 5), trypsin-like (Beta 2), and caspase-like (Beta 1). Our long-term goal is to understand the precise roles of these active sites as targets of anti-neoplastic agents and to use this information to design new, more potent, less toxic drugs of this class. Bortezomib was developed as an inhibitor of the Beta 5 site, which has long been considered the only suitable target for inhibition. However, bortezomib also inhibits the (Beta 1 site, and we have recently obtained data showing that inhibition of the Beta 1 site is needed to achieve maximal cytotoxicity. Based on these data and on critical review of the literature, we hypothesize that (a) all three active sites are drug molecular targets, (b) inhibition of at least two sites is required to achieve optimal cytotoxicity, (c) the therapeutic windows of proteasome inhibitors depend on which active sites they target, and (d) the exact pathways by which proteasome inhibitors induce apoptosis in malignant cells depend on which active sites they target. We will test this hypothesis in multiple myeloma and breast cancer cells using unique, cell-permeable, specific inhibitors of proteasome catalytic sites that we have developed and are developing. The specific aims of this proposal are as follows: (1) To determine the growth inhibitory and cytotoxic effects of specific inhibitors of (Beta 5, Beta1, and Beta 2 catalytic sites, alone and in combination with each other, on cells derived from multiple myeloma and breast cancers, on immortalized and transformed human mammary epithelial cells, and on human peripheral blood lymphocytes; (2) To determine whether the mechanisms by which proteasome inhibitors kill multiple myeloma cells depend on the catalytic sites being targeted by these agents; The results of these studies will define what active-site pharmacological specificities proteasome inhibitors must have to achieve optimal anti-neoplastic activity and therapeutic windows. Taken together, these studies will provide a strong rationale for development of novel inhibitors with desired molecular pharmacological properties. Such compounds have potentially broad applicability for cancer therapy.

描述（由申请人提供）：蛋白质上的蛋白质降解在恶性细胞的增殖中起着至关重要的作用。蛋白酶体抑制剂Velcade（Bortezomib，PS-341）用于治疗多发性骨髓瘤，并正在临床试验中以治疗其他癌症。蛋白酶体具有三种类型的活性位点：类似胰凝乳蛋白酶样（β5），类似胰蛋白酶样（β2）和类似caspase的（β1）。我们的长期目标是了解这些活跃部位作为抗塑性剂的目标的确切作用，并使用此信息来设计该类别的新，更有效，毒性较小的药物。硼替佐米是作为β5位点的抑制剂而开发的，长期以来，它一直被认为是唯一合适的抑制靶标。 However, bortezomib also inhibits the (Beta 1 site, and we have recently obtained data showing that inhibition of the Beta 1 site is needed to achieve maximal cytotoxicity. Based on these data and on critical review of the literature, we hypothesize that (a) all three active sites are drug molecular targets, (b) inhibition of at least two sites is required to achieve optimal cytotoxicity, (c) the蛋白酶体抑制剂的治疗窗口取决于它们靶向的活性部位，以及（d）蛋白酶体抑制剂在恶性细胞中诱导凋亡依赖于它们靶向的活性部位，我们将使用独特的细胞癌细胞中使用独特的，特异性的，特异性的蛋白酶蛋白质蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白。以下内容：（1）确定特定抑制剂的生长抑制和细胞毒性作用（Beta 5，Beta1和Beta 2催化部位，单独并彼此结合，对来自多发性骨髓瘤和乳腺癌的细胞，对永生和转化的人类乳腺外皮细胞以及对人类疗效的人类乳腺癌的细胞，以及对人类乳腺癌的血液plympheral lympheral lympheral lympheral； （2）确定蛋白酶体抑制剂杀死多发性骨髓瘤细胞的机制是否取决于这些药物的催化位点；这些研究的结果将定义哪些活性部位药理特异性蛋白酶体抑制剂必须实现最佳的抗肿瘤活性和治疗窗口。综上所述，这些研究将为开发具有所需分子药理特性的新型抑制剂提供有力的理由。此类化合物具有潜在的广泛适用于癌症治疗。