Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs

通过 MetalloPROTAC 靶向金属依赖性表观遗传调节剂

基本信息

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
项目类别：
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

项目摘要

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“无法药物化”。 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该计划提出了通过提供一个重要的下一步来实现这些目标。用于快速开发和表征能够诱导的异双功能分子的平台在这个项目中，我们的团队利用新的分子靶向剂降解癌症相关的金属酶。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）的最终目标是实现 jumonji C 结构域的异构体选择性降解含有赖氨酸脱甲基酶的当前抑制保守催化结构域 Jumonjis (JMJC) 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，与活性位点中的铁离子协调，靶向 JMJC 的组蛋白结合辅助结构域生成。然而，没有任何抑制剂被证明仅对一种异构体具有选择性。我们选择采取有针对性的降解方法来增加 JMJC 的表面积。通过招募 E3 连接酶来实现外周相互作用该程序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金属蛋白（“MetalloPROTACs”）通过合理的 MBP 和连接器设计，并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。