Selective inhibition of COPZ1 in PDAC cells

PDAC 细胞中 COPZ1 的选择性抑制

• 批准号: 10666703
• 负责人: Roberto Gomes
• 金额: $ 22.63万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666703
• 关键词: Address; Animal Experiments; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Autophagocytosis; Binding; Binding Sites; Biodistribution; Biology; Cancer Etiology; Carrier Proteins; Cell Cycle; Cell Cycle Stage; Cell Death; Cell Death Induction; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cessation of life; Chemistry; Coatomer Protein; Complex; Computers; DNA; Dependence; Diagnostic; Disease; Disease remission; Drug Design; Drug Kinetics; Drug usage; Endoplasmic Reticulum; Endosomes; Excision; Generations; Genes; Geometry; Goals; Golgi Apparatus; Guanosine; Guanosine Triphosphate; Health; Homeostasis; Human; Hydrophobicity; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Mediating; Neoplasm Metastasis; Normal Cell; Operative Surgical Procedures; Organic Chemistry; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Positioning Attribute; Proliferating; Protein Complex Subunit; Protein Isoforms; Proteins; Recurrence; Relapse; Research; Resectable; Rest; Secretory Vesicles; Stress; Study models; Survival Rate; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Failure; Tumor Cell Line; Validation; Viral; antitumor effect; cancer therapy; carcinogenesis; cell killing; chemical synthesis; conventional therapy; design; drug action; drug candidate; drug development; drug synthesis; efficacy evaluation; endoplasmic reticulum stress; improved; inhibitor; model design; molecular modeling; mouse model; neoplastic cell; new technology; novel strategies; pancreatic ductal adenocarcinoma cell; protein complex; prototype; response; retrograde transport; small molecule; tumor; tumor eradication; virtual screening

Project Summary The common approaches in cancer treatment involve drugs that act on DNA or proteins involved in cell proliferation. Regrettably, such drugs are (a) not selective to tumor cells causing damage in normal cells, and (b) ineffective in killing nondividing tumor cells, which can cause tumor relapse after the initial remission, leading to therapy failure. In our search for a protein that can kill tumor cells regardless of theirs proliferating status, we noted that the Protein Complex of Secretory Vesicle I (COPI) is involved in retrograde transport of proteins in the ER-Golgi secretory pathway, endosome maturation, and autophagy homeostasis. Its depletion leads to abortive autophagy, ER stress, unfolded protein response (UPR), and apoptosis. Almost all of the COPI components are expressed at the same levels in both normal and tumor cells. However, the coatomer protein complex I subunit 2 (COPZ2) is drastically downregulated in the tumor cells. Interestingly, in normal cells, the inhibition of the coatomer protein complex subunit 1 (COPZ1, an isoform of COPZ2) does not affect COPI function. However, the silencing of COPZ1 and COPZ2 simultaneously led to the loss of COPI function and, consequently, cell death. Then, COPZ2 deficiency indicates tumor cells' dependency on COPZ1. Therefore, selective COPZ1 inhibition in COPZ2-deficient tumor cells can potentially overcome the therapy failure problem. We will design a promising lead compound to inhibit COPZ1 in COPZ2-deficient tumor cells, selectively killing tumor cells over healthy cells. Our first-generation synthesized COPZ1 inhibitors (based on virtual screening) showed good selectivity against PDAC. Our central objective is to develop the second-generation small- molecule-based COPZ1 inhibitors that can kill PDAC cells selectively over normal cells by merging molecular modeling, chemical Synthesis, cellular mechanistic studies, and animal experiments. Specifically, we will improve COPZ1 selectivity by conjugating small organic molecules to interact with a secondary binding site. We hypothesize that the tumor cell death induced by selective inhibition of COPZ1 could lead the proliferating and nondividing tumor cells to apoptosis but not normal cells.

项目摘要 癌症治疗的常用方法包括作用于dna或细胞中的蛋白质的药物。 扩散。令人遗憾的是，这些药物(A)对造成正常细胞损害的肿瘤细胞没有选择性，以及 (B)在杀死未分裂的肿瘤细胞方面效果不佳，这可能导致肿瘤在最初缓解后复发，导致 治疗失败的原因。在我们寻找一种可以杀死肿瘤细胞的蛋白质的过程中，无论它们的增殖状态如何，我们 注意到分泌囊泡I的蛋白复合体(COPI)参与了蛋白质的逆行转运。 内质网-高尔基体分泌途径、内体成熟和自噬动态平衡。它的枯竭导致 流产的自噬、内质网应激、未折叠蛋白反应(UPR)和细胞凋亡。几乎所有的COPI 各组分在正常细胞和肿瘤细胞中的表达水平相同。然而，辅酶蛋白 在肿瘤细胞中，复合体I亚单位COPZ2(2)表达显著下调。有趣的是，在正常细胞中， 抑制辅酶蛋白复合体1(COPZ1，COPZ2的异构体)不会影响COPI值 功能。然而，COPZ1和COPZ2的沉默同时导致COPI功能的丧失， 结果，细胞死亡。然后，COPZ2缺乏表明肿瘤细胞对COPZ1的依赖。因此， 在COPZ2缺陷的肿瘤细胞中选择性抑制COPZ1可以潜在地克服治疗失败的问题。 我们将设计一种有前景的先导化合物来抑制COPZ2缺陷的肿瘤细胞中的COPZ1，选择性地杀伤 肿瘤细胞胜过健康细胞。我们的第一代合成COPZ1抑制剂(基于虚拟筛选) 对PDAC表现出良好的选择性。我们的中心目标是开发第二代小型- 基于分子的COPZ1抑制剂可通过分子融合选择性地杀伤PDAC细胞 建模、化学合成、细胞力学研究和动物实验。具体来说，我们将 通过结合小有机分子与二级结合位点相互作用来提高COPZ1的选择性。我们 假设选择性抑制COPZ1诱导的肿瘤细胞死亡可能导致肿瘤细胞的增殖和 未将肿瘤细胞分裂为凋亡细胞，而不是正常细胞。