Characterization and suppression of resistance to NEDD8 E1 inhibition

NEDD8 E1 抑制抗性的表征和抑制

基本信息

批准号：
8785107
负责人：
Matthew Petroski
金额：
$ 21.21万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785107
关键词：
Adenosine Adverse effects Affinity Antineoplastic Agents Binding Biochemical Biological Assay Bortezomib Cancer Patient Cancer cell line Categories Cell Death Cell Survival Cells Clinical Data Clinical Trials Cullin Proteins Data Development Drug Targeting Drug resistance Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Experimental Neoplasms Exposure to FDA approved Future Generations Goals Health Knowledge Ligands Malignant Neoplasms Multienzyme Complexes Mutation Non-Hematologic Malignancy Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Positioning Attribute Post-Translational Protein Processing Proteasome Inhibitor Publishing Relapse Reporting Research Research Project Grants Resistance Scanning System Testing Therapeutic Time Toxic effect Ubiquitin Ubiquitin Like Proteins Velcade Work analog base cancer cell cancer therapy clinical efficacy cytotoxicity drug discovery drug testing enzyme activity inhibitor/antagonist innovation insight novel pre-clinical preclinical study pressure prevent programs research study resistance mechanism response screening small molecule success sulfamate therapeutic target tool tumor microenvironment ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The successes of proteasome inhibitors bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) as FDA-approved cancer drugs have invigorated efforts to devise new cancer therapeutics targeting upstream pathways involving enzymes of ubiquitin and ubiquitin-like protein modification systems. Our long-term goal is to provide therapies that inhibit the NEDD8 system and the major NEDD8 targets cullin-RING ubiquitin ligases to directly benefit cancer patients. The NEDD8-activating enzyme (NAE) inhibitor MLN4924 is currently the most advanced of these potential new classes of drugs. MLN4924 has extensive published pre-clinical data demonstrating strong anti-cancer efficacy and several Phase 1 clinical trials are in progress for hematologic and advanced non-hematologic malignancies. Given the clear benefit MLN4924 provides by selectively inducing cancer cell death with no noted toxicities or side-effects on experimental cancers, it remains highly significant to understand how cells respond to NEDD8 system inhibition. As an important step towards this goal and in response to PAR-12-145 NCI Exploratory/Developmental Research Grant Program, the overall objective of this proposed study is to use insight derived from experiments examining on-target MLN4924 resistance to identify new NAE inhibitors that function through mechanisms of action distinct from MLN4924. Through our strong preliminary data, we have devised a highly innovative strategy that uniquely positions us to describe the types of on-target mutations possible for MLN4924 resistance. We have also generated a new screening assay based on differential scanning fluorimetry. This uses a ligand competition strategy to evaluate the mechanism of action of molecules that bind NAE. Our central hypothesis is that the diversity of biochemical changes in NAE sufficient for cancer cell resistance to MLN4924 can be overcome by small molecules that inhibit NAE through mechanisms not involving the enzyme's catalytic pocket. To test this hypothesis and achieve the overall objective of the research, two Specific Aims are proposed: 1) to characterize the biochemical diversity of MLN4924-resistant forms of NAE and 2) to identify small molecule inhibitors of these drug-resistant NAE complexes. IMPACT: This work is highly innovative with direct translational relevance due to the extraordinary opportunity it provides to describe MLN4924 resistance mechanisms in detail before they are reported in relapsed patients and to use this information to discover new NAE inhibitors that function through distinct mechanisms of action. Collectively, these efforts will significantly contribute to providing much needed new treatment options for cancer patients.

DESCRIPTION (provided by applicant): The successes of proteasome inhibitors bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) as FDA-approved cancer drugs have invigorated efforts to devise new cancer therapeutics targeting upstream pathways involving enzymes of ubiquitin and ubiquitin-like protein modification systems.我们的长期目标是提供抑制NEDD8系统的疗法，而主要的NEDD8靶向Cullin环泛素连接酶直接使癌症患者受益。 NEDD8激活酶（NAE）抑制剂MLN4924目前是这些潜在的新药物中最先进的。 MLN4924已广泛发表的临床前数据，证明了强烈的抗癌功效，而血液学和晚期非血液学恶性肿瘤正在进行多项1期临床试验。鉴于MLN4924的明显益处是通过选择性诱导癌细胞死亡而没有注意到实验性癌症的副作用而提供的，因此了解细胞对NEDD8系统抑制作用的反应仍然非常重要。为了朝着这一目标迈出的重要一步，并响应PAR-12-145 NCI探索性/发展研究赠款计划，这项拟议研究的总体目标是利用从检查目标MLN4924耐药性的实验中获得的见解，以识别通过MLN4924与MLN4924相关的作用机制起作用的新NAE NAE抑制剂。通过我们强大的初步数据，我们设计了一种高度创新的策略，该策略唯一地定位了MLN4924抗性可能的靶向突变类型。我们还基于差异扫描荧光法生成了一个新的筛选分析。这使用配体竞争策略来评估结合NAE的分子的作用机理。我们的中心假设是，可以通过不涉及酶催化口袋的机制抑制NAE的小分子来克服NAE的生物化学变化的多样性。为了检验这一假设并实现研究的总体目标，提出了两个具体的目的：1）表征MLN4924耐NAE的生化多样性和2）识别这些耐药NAE配合物的小分子抑制剂。影响：这项工作具有很高的创新性，直接转化相关性是由于它提供的特殊机会来描述MLN4924的抗药性机制，然后再报告这些信息在复发患者中，并使用这些信息来发现通过不同的作用机制起作用的新NAE抑制剂。总的来说，这些努力将极大地为癌症患者提供急需的新治疗选择。