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使 虽然癌蛋白的研究已经取得了进展，但目前的干预策略已经使许多蛋白质组“无法治疗”。响应于 NCI已经认识到PAR-22-216中概述的这一挑战， 基于肿瘤发生过程中激活的特异性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下一步， 用于快速开发和表征能够诱导 用新的分子靶向剂降解癌症相关的金属酶。在这个项目中，我们的团队 将开发蛋白水解靶向嵌合体（PROTAC），含有最先进的金属结合 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。抑制Jumonjis（JMJC）保守催化结构域的当前策略 涉及用抑制剂靶向JMJC的α-酮基谷氨酸（2 OG）底物接受活性位点， 与活性位点的铁离子配位。靶向JMJC的组蛋白结合辅助结构域产生 额外的异构体选择性。然而，没有抑制剂显示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 通过募集E3连接酶的外周相互作用。这个程序将演示如何潜在的蛋白质- 由这些嵌合体诱导的蛋白质相互作用可被利用来诱导选择性降解 通过合理的MBP和接头设计，将金属蛋白（“MetalloPROTAC”）转化为蛋白质，并将作为 研究癌症生物学，并为未来治疗药物的开发奠定基础。