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。尽管最近的努力已经确定了有能力失活的方法 癌蛋白，当前的干预策略使大部分蛋白质组“不可用”。作为回应 NCI通过激励新的发展，认识到这一挑战是PAR-22-216中概述的 基于在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。该计划建议通过提供一个重要的下一步来实现这些目标 快速发展和表征能够诱导的异性锻炼分子的平台 与新分子靶向剂的癌症相关金属酶的降解。在这个计划中，我们的团队 将开发靶向嵌合体（protac）的蛋白水解，其中含有最先进的金属结合 具有实现Jumonji C域的同工型选择降解的最终目标的药算术（Mbps） 含有赖氨酸脱甲基酶。当前抑制组成催化域Jumonjis（JMJC）的策略 涉及靶向具有抑制剂的JMJC的α-酮谷氨酸（2oG）底物的活性位点 与活性位点中的铁离子进行协调。靶向JMJCS的组蛋白结合辅助域域生成 其他同工型选择性。但是，尚无抑制剂仅适用于一个同工型的选择性 JMJCS。我们选择采用靶向降解方法，以增加 通过募集E3连接酶的外围相互作用。该程序将证明潜在蛋白质如何 这些嵌合体诱导的蛋白质相互作用可以利用以诱导选择性降解 金属蛋白（金属蛋白酶蛋白）通过合理的MBP和接头设计，将作为该平台 研究癌症生物学的研究，并为未来的治疗剂开发奠定了基础。