Inhibitors of Oxidative Protein Folding For The Treatment of Cancer

用于治疗癌症的氧化蛋白折叠抑制剂

• 批准号: 10197861
• 负责人: Nathan G. Dolloff
• 金额: $ 47.55万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197861
• 关键词: Address; Affinity; Antineoplastic Agents; Antitumor Response; Apoptotic; Automobile Driving; Binding; Biochemical; Biological Assay; CASP3 gene; Cancer Model; Cell model; Cellular Assay; ChIP-seq; Chemicals; Chemosensitization; Chromatin Structure; Clinic; Clinical Trials; Coupled; Coupling; Crystallization; Data; Development; Diagnosis; Docking; Drug Combinations; Drug Targeting; Epigenetic Process; Evaluation; Exhibits; FDA approved; Family member; Future; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Hematologic Neoplasms; Heme; Histologic; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Indenes; KRASG12D; Knowledge; Lead; Literature; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Oncology; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Play; Pre-Clinical Model; Protein Disulfide Isomerase; Proteins; RNA Binding; RNA Polymerase II; Research; Resistance; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Solid; Specificity; Structure; Survival Rate; Therapeutic; Translating; Treatment Protocols; Work; X-Ray Crystallography; activating transcription factor 3; analog; anticancer activity; cancer cell; cancer clinical trial; cancer therapy; cancer type; chromatin immunoprecipitation; clinical development; comparative; drug candidate; drug structure; effective therapy; endoplasmic reticulum stress; epigenetic drug; expectation; experimental study; in vivo; inhibitor/antagonist; innovation; insight; knock-down; mouse model; nanomolar; new combination therapies; novel; novel drug class; novel therapeutic intervention; novel therapeutics; overexpression; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pharmacodynamic biomarker; pre-clinical; programs; promoter; protein folding; proteostasis; response biomarker; simulation; small molecule; synergism; therapeutic evaluation; transcriptome sequencing; tumor

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective therapies. The long-term goal of this research program is to discover new therapeutic approaches and drug combinations for the treatment of PDAC and other incurable cancers. Previous studies by our group identified a new class of protein disulfide isomerase (PDI) inhibitor with activity in a variety of solid and hematological cancer types including PDAC. PDIs are emerging oncology targets that play a critical role in the proper folding of newly synthesized proteins. PDIs are overexpressed in a variety of tumor types and are attractive oncology targets. In an unbiased screen of FDA-approved oncology drugs, we found this new class of drug could dramatically enhance the activity of histone deacetylase (HDAC) inhibitors with the strongest synergy being observed in PDAC models. The specific objectives of this study are: (1) to uncover the molecular mechanism responsible for the remarkable synergy between PDI and HDAC inhibitors in PDAC, (2) to resolve binding of novel PDI inhibitors to their target using X-ray crystallography, and (3) to demonstrate the preclinical anti-cancer activity of lead PDI inhibitors as single agents and in combination with HDAC inhibitors in genetically engineered mouse models (GEMMs) of PDAC. These aims are built on clear rationale from the existing literature and strong preliminary data. This work is innovative because we investigate the activity and mechanism of a new drug candidate and new treatment combination for the treatment of PDAC, a cancer in desperate need of new therapies. It is our expectation that this work will deliver a new drug candidate and combination treatment regimen for the treatment of PDAC, provide insight into the druggability of an emerging cancer drug target in PDI, and uncover molecular mechanisms that enhance the activity of HDAC inhibitors.

胰腺导管腺癌 (PDAC) 是胰腺癌最常见的形式，是最常见的胰腺癌之一。 最致命的癌症形式。生存率低主要是由于 PDAC 诊断已处于晚期 且缺乏有效的治疗方法。该研究计划的长期目标是发现新的治疗方法 治疗 PDAC 和其他无法治愈的癌症的方法和药物组合。之前的研究 我们的团队鉴定出一类新型蛋白质二硫键异构酶 (PDI) 抑制剂，在多种固体中具有活性 和血液癌症类型，包括 PDAC。 PDI 是新兴的肿瘤学靶点，在 新合成蛋白质的正确折叠。 PDI 在多种肿瘤类型中过度表达， 有吸引力的肿瘤学目标。在对 FDA 批准的肿瘤药物的公正筛选中，我们发现了这一新类别 药物可以显着增强组蛋白脱乙酰酶（HDAC）抑制剂的活性，具有最强的 在 PDAC 模型中观察到协同作用。本研究的具体目标是：（1）揭示 PDI 和 HDAC 抑制剂在 PDAC 中显着协同作用的分子机制，(2) 使用 X 射线晶体学解析新型 PDI 抑制剂与其靶标的结合，以及 (3) 证明 主要 PDI 抑制剂作为单药以及与 HDAC 抑制剂联合使用的临床前抗癌活性 在 PDAC 基因工程小鼠模型 (GEMM) 中。这些目标建立在明确的理由之上 现有文献和强有力的初步数据。这项工作具有创新性，因为我们调查了这项活动并 治疗 PDAC（一种癌症）的新候选药物和新治疗组合的机制 迫切需要新疗法。我们期望这项工作将提供一种新的候选药物 治疗 PDAC 的联合治疗方案，提供了对新兴药物的成药性的深入了解 PDI 中的癌症药物靶点，并揭示增强 HDAC 抑制剂活性的分子机制。