Small molecule CXCR4 modulators as molecular probes for studying AML

小分子 CXCR4 调节剂作为研究 AML 的分子探针

基本信息

批准号：
9099791
负责人：
RICHARD J MILLER
金额：
$ 53.99万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099791
关键词：
AMD3100 Acute Acute Myelocytic Leukemia Adverse effects Agonist Antineoplastic Agents Autoimmune Diseases Behavior Biological Biological Assay Biological Process Biological Testing Biology Blood Circulation Bone Marrow CXCL12 gene CXCR4 Receptors CXCR4 gene Cell Line Cells Chemosensitization Chemotaxis Combined Modality Therapy Computer Simulation Coupled Development Disease Drug Design Drug Kinetics Extracellular Matrix Family G-Protein-Coupled Receptors Generations Goals HIV HIV-1 Health Hematologic Neoplasms Hematopoietic Stem Cell Mobilization Hematopoietic stem cells Human In Vitro Inflammation Investigation Lead Left Leukemic Cell Leukocytosis Ligands Malignant Neoplasms Mediating Molecular Molecular Probes Myeloid Leukemia Pathogenesis Pathologic Processes Pathway interactions Patients Peptides Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Processes Physiology Play Population Heterogeneity Process Property Regimen Reporting Residual Neoplasm Role Series Signal Transduction Site Solid Neoplasm Stem cells Stromal Cell-Derived Factor 1 Stromal Cells System Therapeutic Therapeutic Effect Therapeutic Human Experimentation Toxic effect Transplantation Tumor Cell Line Xenograft Model base cell motility chemokine chemokine receptor chemotherapy design improved in vivo innovation insight lead series leukemia neoplastic cell novel strategies novel therapeutic intervention outcome forecast protective effect receptor receptor binding receptor internalization release of sequestered calcium ion into cytoplasm research study response screening small molecule therapeutic development tool trafficking tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in diverse physiological and pathological processes such as HIV infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. Although the CXCR4 receptor and its unique ligand SDF-1 have been widely studied, all small molecule modulators of the SDF-1/CXCR4 axis have been antagonists. The lack of available small molecule agonists constitutes a substantial gap in the ability to probe the biology of CXCR4. Using new in silico screening strategies, we have recently discovered the first series of small molecule CXCR4 agonists and have demonstrated their unique behavior in a variety of biological settings. Notably, our small molecules cause internalization of the CXCR4 receptor, a strong chemotactic response, and chemosensitization of tumor cell lines. Development of these small molecule agonists and structurally related antagonists will provide a unique and powerful means to study the function of the CXCR4 receptor and how this relates to disease processes. Acute myeloid leukemia (AML) is a group of myeloid leukemias with a very aggressive and fatal course if left untreated. The bone marrow (BM) microenvironment provides an important protective effect against chemotherapy and disruption of this interaction renders AML cells sensitive to chemotherapy in vitro and in vivo. The SDF-1/CXCR4 axis plays a key role in regulating stem cell mobilization and trafficking and its expression has been shown to negatively correlate to the prognosis of many cancers. Our lead agonist significantly enhances chemosensitivity of multiple leukemic cell lines to several chemotherapies, suggesting that CXCR4 agonists may provide a novel therapeutic approach for the treatment of AML. The overall goal of this project is to optimize small molecule CXCR4 agonist probes and characterize their activity against the CXCR4 receptor and AML in vitro and in vivo. Our unique small molecule CXCR4 agonists and antagonists give us a set of unique molecular tools to understand how CXCR4 receptor pharmacology impacts AML. In Aim 1 we will use rational medicinal chemistry to optimize our lead series for potency and drug-like properties, incorporating in silico design and robust biological testing into an iterative process. We will characterize new CXCR4 modulators in Aim 2 by evaluating their behavior against a number of in vitro systems including calcium mobilization, receptor binding, receptor internalization, chemotaxis, and signaling through various pathways. Aim 3 will evaluate the effects of CXCR4 modulation on AML using leukemia cell lines and primary human tumor cells as well as in vivo using patient-derived xenografts models of AML. The proposed studies will generate new molecular probes to investigate the pharmacology of CXCR4 and understand how this important receptor is involved in AML. These results will provide new insights into AML and potentially open up new avenues for therapeutic development.

描述：趋化因子CXCL12（SDF-1）及其同源受体CXCR4参与了HIV感染性，炎症，肿瘤发生，干细胞迁移和自身免疫性疾病等过程。激动剂在使用新的筛选策略中探测CXCR4的生物学的差距很大，我们最近发现了第一辑的小分子CXCR4激动剂，并在各种生物群中证明了它们独特的IOR小分子引起CXCR4受体的内在化，肿瘤细胞线的血压敏化。未经治疗。这种相互作用的破坏使AML细胞在体外和体内进行化学疗法。 UR铅激动剂的意义增强了多个白血病细胞系toothapies，这表明CXCR4激动剂是一种治疗AML治疗的新型治疗方法。在体内。我们独特的小分子CXCR4激动剂和拮抗剂为我们提供了一系列独特的分子工具，以了解CXCR4受体药理学如何影响AML，以实现效力和类似药物的特性。 AIM 2中的新CXCR4调节剂对许多体外系统的动员，受体不体化，趋化性和信号通过各种途径，以及使用患者衍生的AML模型拟议的研究将产生新的分子探针来研究CXCR4的药理学，并了解这些重要的受体如何参与AML。