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：
10653861
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/10653861
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 Combined Modality Therapy Coupled Coupling 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 Acetylation Histone Deacetylase Inhibitor In Vitro Indenes KRASG12D Knowledge Lead Literature Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator Metabolic Modeling Molecular Oncology Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Play Pre-Clinical Model Protein Biosynthesis Protein Disulfide Isomerase 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 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.

胰腺癌腺癌（PDAC）是胰腺癌最常见的形式，是其中一种最致命的癌症形式。存活率差主要是由于诊断为PDAC的后期缺乏有效的疗法。该研究计划的长期目标是发现新的治疗性用于治疗PDAC和其他无法治愈的癌症的方法和药物组合。先前的研究我们小组确定了一种新的蛋白质二硫化物异构酶（PDI）抑制剂，其活性在各种固体中以及包括PDAC在内的血液癌类型。 PDI是新兴的肿瘤学目标，在新合成蛋白的适当折叠。 PDI在多种肿瘤类型中过表达，并且是有吸引力的肿瘤学目标。在FDA批准的肿瘤学药物的公正屏幕中，我们发现了这个新类药物的大大增强了组蛋白脱乙酰基酶（HDAC）抑制剂的活性在PDAC模型中观察到协同作用。这项研究的具体目标是：（1）揭示负责PDAC中PDI和HDAC抑制剂之间显着协同作用的分子机制，（2）使用X射线晶体学解决新型PDI抑制剂与目标的结合，（3）证明铅PDI抑制剂作为单个药物的临床前抗癌活性，并与HDAC抑制剂结合在PDAC的基因工程小鼠模型（GEMM）中。这些目标是建立在明确的基本原理上的现有文献和强大的初步数据。这项工作具有创新性，因为我们调查了活动和新药的机制和新的治疗组合用于治疗PDAC，一种癌症迫切需要新疗法。我们期望这项工作将提供新药候选人，并且用于治疗PDAC的联合治疗方案，提供有关新兴的吸毒性的见解 PDI中的癌症药物靶标，并发现增强HDAC抑制剂活性的分子机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PDI inhibitor LTI6426 enhances panobinostat efficacy in preclinical models of multiple myeloma.

DOI：
10.1007/s00280-022-04425-3
发表时间：
2022-05
期刊：
CANCER CHEMOTHERAPY AND PHARMACOLOGY
影响因子：
3
作者：
Robinson, Reeder M.;Basar, Ashton P.;Reyes, Leticia;Duncan, Ravyn M.;Li, Hong;Dolloff, Nathan G.
通讯作者：
Dolloff, Nathan G.

Selective targeting of CD38 hydrolase and cyclase activity as an approach to immunostimulation.

DOI：
10.1039/d1ra06266b
发表时间：
2021-10-08
期刊：
RSC ADVANCES
影响因子：
3.9
作者：
Benton, Thomas Z.;Mills, Catherine M.;Turner, Jonathan M.;Francis, Megan J.;Solomon, Dalan J.;Burger, Pieter B.;Peterson, Yuri K.;Dolloff, Nathan G.;Bachmann, Andre S.;Woster, Patrick M.
通讯作者：
Woster, Patrick M.