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.

项目总结。虽然最近的努力已经确定需要能够使