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Project 4

项目4

基本信息

批准号：
10230530
负责人：
Taosheng Chen
金额：
$ 2.56万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10230530
关键词：
Acute Erythroblastic Leukemia Acute Myelocytic Leukemia Acute leukemia Binding Biological Assay Biophysics C-terminal Cell Nucleus Cell model Cells Cellular Assay Chemicals Child Chromatin Collection DNA Binding Domain Development Disease Epigenetic Process Experimental Models Family Fluorescence Resonance Energy Transfer Fusion Oncogene Proteins Gene Expression Genetic Transcription Goals HOXA9 gene Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Histones Homeobox Human In Vitro Leukemic Cell Libraries Lysine Metabolic Methods Modeling Modernization Mus N-terminal NMR Spectroscopy NUP98 gene Nuclear Nuclear Pore Complex Oncogenes Pediatric Hematology Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Pre-Clinical Model Property Protac Regulator Genes Remission Induction Therapy Saint Jude Children&apos s Research Hospital Solubility Structure Surface Testing Therapeutic Transplantation X-Ray Crystallography base biophysical techniques cell transformation chemical synthesis in vivo inhibitor/antagonist leukemia mouse model novel therapeutic intervention outcome forecast prevent recruit screening small molecule small molecule inhibitor submicron therapeutic development transcription factor treatment strategy ubiquitin-protein ligase

项目摘要

Project 4/Summary NUP98-fusion oncogenes (eg, NUP98-HOXA9, -KDM5A & -NSD1) are associated with several pediatric hematological malignancies (eg, AML; 6-10%; and AEL; 20%) characterized by poor prognosis. All of these oncogenes fuse the N-terminal FG-repeat domain of the nucleoporin NUP98 to chromatin binding domains from a variety of transcriptional and epigenetic regulators (e.g., the histone binding PHD3 domain of KDM5A). Endogenous NUP98 primarily localizes to the nuclear pore complex, with its intrinsically disordered FG-repeat domain (~500 residues) filling the central pore. In contrast, NUP98 fusion oncoproteins (FOs) enter the nucleus, bind to chromatin and cause the formation of numerous, sub-micron sized nuclear puncta. Importantly, these puncta recruit epigenetic and transcriptional regulators to developmental regulatory genes, notably the HOX family, activate aberrant gene expression, and transform hematopoietic cells. Leukemias harboring NUP98 FOs are treated with standard AML-based remission induction therapy, with intensification/transplantation for suboptimally responsive disease, but prognosis is generally poor. Therefore, there is great need for new therapeutic strategies for treatment of NUP98 FO-driven leukemias. While the N- terminal domain of NUP98 FOs is considered undruggable because it is intrinsically disordered, their folded C- terminal domains offer opportunities for therapeutic development. For example, binding of the PHD3 domain within the NUP98-KDM5A FO to di-and tri-methylated lysine 4 of Histone 3 (H3K4-Me2/3) is required for rewiring of the epigenetic state of hematopoietic cells and their transformation. Further, deletion of the HOXA9 DNA binding domain from the NUP98-HOXA9 FO alters nuclear puncta formation and prevents cell transformation. Thus, therapeutic strategies targeting the interactions of these folded domains with chromatin have potential to inhibit cell transformation by NUP98 FOs. Here, we propose to develop small molecules that bind the KDM5A PHD3 domain and inhibit its binding to H3K4-Me2/3 (Aims 1 & 2). We further propose to adapt PHD3 domain binders and inhibitors using the PROTAC (PROteolysis-TArgeting Chimaera) strategy to induce degradation of NUP98-KDM5A in cells (Aim 2). The inhibitors and PROTACs we develop will be tested against murine and human cellular models, and in vivo murine models of NUP98-KDM5A-driven AML.

项目4 /总结