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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

基本信息

批准号：
10437641
负责人：
Nathan G. Dolloff
金额：
$ 49.08万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
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/10437641
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 gene network in vivo inhibitor inhibitor therapy 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

项目摘要

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，是胰腺癌的主要类型之一。最致命的癌症存活率低主要是由于诊断为PDAC的晚期缺乏有效的治疗方法。这项研究计划的长期目标是发现新的治疗方法，用于治疗PDAC和其他不可治愈的癌症的方法和药物组合。以前的研究我们的小组鉴定了一类新的蛋白质二硫键异构酶（PDI）抑制剂，其在多种固体中具有活性，和血液癌症类型，包括PDAC。PDIs是新兴的肿瘤学靶点，新合成蛋白质的正确折叠。PDIs在多种肿瘤类型中过表达，有吸引力的肿瘤靶点。在对FDA批准的肿瘤药物的无偏见筛选中，我们发现了这类新药物，的药物可以显着提高组蛋白去乙酰化酶（HDAC）抑制剂的活性，在PDAC模型中观察到协同作用。本研究的具体目标是：（1）揭示负责PDAC中PDI和HDAC抑制剂之间显著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）证明先导PDI抑制剂作为单一药剂和与HDAC抑制剂组合的临床前抗癌活性在PDAC的基因工程小鼠模型（GEMM）中。这些目标是建立在明确的理由，现有的文献和强大的初步数据。这项工作是创新的，因为我们调查的活动，用于治疗PDAC的新候选药物和新治疗组合的机制，PDAC是一种癌症，迫切需要新的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，提供了对一种新兴的癌症药物靶向PDI，并揭示增强HDAC抑制剂活性的分子机制。