Characterization and suppression of resistance to NEDD8 E1 inhibition

NEDD8 E1 抑制抗性的表征和抑制

• 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
• 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

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.

描述（由申请人提供）：蛋白酶体抑制剂硼替佐米 (Velcade(R)) 和卡非佐米 (Kyprolis(R)) 作为 FDA 批准的抗癌药物所取得的成功，激发了设计针对涉及泛素酶和泛素样蛋白修饰系统的上游途径的新癌症疗法的努力。我们的长期目标是提供抑制 NEDD8 系统和 NEDD8 主要靶点 cullin-RING 泛素连接酶的疗法，以直接造福癌症患者。 NEDD8 激活酶 (NAE) 抑制剂 MLN4924 是目前这些潜在新类别药物中最先进的。 MLN4924已发表的大量临床前数据证明了其强大的抗癌功效，并且针对血液系统和晚期非血液系统恶性肿瘤的多项一期临床试验正在进行中。鉴于 MLN4924 通过选择性诱导癌细胞死亡而提供明显的益处，并且对实验癌症没有明显的毒性或副作用，因此了解细胞如何响应 NEDD8 系统抑制仍然非常重要。作为实现这一目标的重要一步，并响应 PAR-12-145 NCI 探索性/发展研究资助计划，这项拟议研究的总体目标是利用从检查靶向 MLN4924 耐药性的实验中获得的见解来识别通过不同于 MLN4924 的作用机制发挥作用的新 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，使我们能够独特地描述 MLN4924 耐药性可能的靶向突变类型。我们还开发了一种基于差示扫描荧光测定法的新筛选方法。该方法使用配体竞争策略来评估结合 NAE 的分子的作用机制。我们的中心假设是，足以使癌细胞对 MLN4924 产生耐药性的 NAE 生化变化的多样性可以通过小分子克服，这些小分子通过不涉及酶催化袋的机制抑制 NAE。为了检验这一假设并实现研究的总体目标，提出了两个具体目标：1）表征 MLN4924 耐药形式的 NAE 的生化多样性；2）鉴定这些耐药 NAE 复合物的小分子抑制剂。影响：这项工作具有高度创新性，具有直接的转化相关性，因为它提供了绝佳的机会，可以在复发患者中报告 MLN4924 耐药机制之前详细描述它们，并利用这些信息来发现通过不同作用机制发挥作用的新 NAE 抑制剂。总的来说，这些努力将极大地有助于为癌症患者提供急需的新治疗选择。