Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs

通过 MetalloPROTAC 靶向金属依赖性表观遗传调节剂

• 批准号: 10722294
• 负责人: Michael D. Burkart
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722294
• 关键词: Acids; Active Sites; Apoptosis; Area; Binding; Biological Assay; Cancer Biology; Catalytic Domain; Cell Proliferation; Cell Survival; Cell physiology; Chimera organism; Chromatin; Clinical; Complex; Coupled; Cues; Cytosine; Development; Diagnosis; Disease; Epigenetic Process; Evaluation; Family; Foundations; Future; Gene Expression Regulation; Genes; Genetic Transcription; Goals; High Prevalence; Histones; Intervention; Ions; Iron; Left; Length; Libraries; Ligand Binding; Ligands; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Metalloproteins; Metals; Methodology; Methylation; Modality; Modification; Molecular Target; National Cancer Institute; Normal Cell; Oncogenic; Oncoproteins; Oxygenases; Peripheral; Persons; Phosphorylation; Post-Translational Protein Processing; Process; Protac; Protein Isoforms; Proteins; Proteome; Regulation; Reporting; Role; Sequence Homology; Signal Pathway; Surface; Technology; Therapeutic Intervention; Ubiquitination; United States; Water; cancer type; cofactor; design; drug discovery; efficacy evaluation; epigenetic regulation; high reward; high risk; histone methylation; histone modification; inhibitor; innovation; interest; lens; malignant breast neoplasm; metalloenzyme; neoplastic cell; novel; novel anticancer drug; pharmacophore; preclinical development; programs; protein degradation; protein protein interaction; rapid technique; recruit; response; small molecule; success; targeted agent; therapeutic development; therapeutic protein; therapeutic target; tumor; tumor progression; tumorigenesis; ubiquitin-protein ligase

Project Summary. While recent efforts have identified the need for methodologies capable of inactivating oncoproteins, current intervention strategies have left much of the proteome “undruggable.” In response the NCI has recognized this challenge as outlined in PAR-22-216 by incentivizing the development of new molecular targeting agents based on specific signaling pathways activated during the process of tumorigenesis or tumor progression. This program proposes an important next step in reaching these goals by providing a platform for the rapid development and characterization of heterobifunctional molecules capable of inducing degradation of cancer related metalloenzymes with new molecular targeting agents. In this program, our team will develop proteolysis targeting chimeras (PROTACs) containing state-of-the-art metal-binding pharmacophores (MBPs) with the ultimate goal of achieving isoform-selective degradation of jumonji C-domain containing lysine demethylases. Current strategies to inhibit conserved catalytic domain Jumonjis (JMJCs) involve targeting the α-ketoglutaric acid (2OG) substrate-accepting active site of JMJCs with inhibitors that can coordinate to the iron ion in the active site. Targeting the histone-binding helper domain of JMJCs generates additional isoform selectivity. However, no inhibitor has been shown to be selective for only one isoform of JMJCs. We have chosen to take a targeted degradation approach in order to increase the surface area of the peripheral interaction by recruiting an E3 ligase. This program will demonstrate how the potential protein- protein interaction induced by these chimeras can be leveraged to induce selective degradation of metalloproteins (`MetalloPROTACs') through rational MBP and linker design and will serve as a platform for the study of cancer biology, as well as laying the foundation for future development of therapeutic agents.

项目摘要。虽然最近的努力已经确定需要能够灭活的方法 对于癌蛋白，目前的干预策略使大部分蛋白质组“无法成药”。作为回应 NCI 已认识到 PAR-22-216 中概述的这一挑战，通过激励新产品的开发 基于肿瘤发生过程中激活的特定信号通路的分子靶向剂 或肿瘤进展。该计划提出了实现这些目标的重要的下一步，即提供 用于快速开发和表征能够诱导的异双功能分子的平台 用新的分子靶向剂降解癌症相关的金属酶。在这个节目中，我们团队 将开发含有最先进金属结合的蛋白水解靶向嵌合体（PROTAC） 药效团 (MBP)，最终目标是实现 Jumonji C 结构域的异构体选择性降解 含有赖氨酸脱甲基酶。目前抑制保守催化结构域 Jumonjis (JMJCs) 的策略 涉及用抑制剂靶向 JMJC 的 α-酮戊二酸 (2OG) 底物接受活性位点， 与活性位点的铁离子配位。靶向 JMJC 的组蛋白结合辅助域会生成 额外的异构体选择性。然而，没有任何抑制剂被证明仅对一种异构体具有选择性。 JMJC。我们选择采取有针对性的降解方法，以增加表面积 通过募集 E3 连接酶来实现外周相互作用。该计划将展示潜在的蛋白质如何 这些嵌合体诱导的蛋白质相互作用可用于诱导选择性降解 通过合理的 MBP 和连接器设计，金属蛋白（“MetalloPROTACs”）将作为一个平台 癌症生物学的研究，并为未来治疗药物的开发奠定基础。