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（申请人提供）：趋化因子CXCL12（SDF-1）及其同源受体CXCR4参与多种生理和病理过程，例如HIV感染、炎症、肿瘤发生、干细胞迁移和自身免疫性疾病。其独特的配体SDF-1已被广泛研究，所有SDF-1/CXCR4轴的小分子调节剂均缺乏可用的拮抗剂。小分子激动剂构成了探索 CXCR4 生物学能力的巨大差距。利用新的计算机筛选策略，我们最近发现了第一批小分子 CXCR4 激动剂，并在各种生物环境中表现出了显着的独特行为。，我们的小分子引起 CXCR4 受体的内化、强烈的趋化反应和肿瘤细胞系的化学敏化，这些小分子激动剂和结构相关的拮抗剂的开发将提供独特的作用。急性髓系白血病 (AML) 是一组髓系白血病，如果不及时治疗，其病程非常具有侵袭性和致命性。对化疗的重要保护作用和这种相互作用的破坏使 AML 细胞对体外和体内化疗敏感。SDF-1/CXCR4 轴在调节干细胞动员和运输及其中发挥着关键作用。 CXCR4 的表达已被证明与许多癌症的预后呈负相关。我们的主要激动剂可显着增强多种白血病细胞系对多种化疗的化疗敏感性，这表明 CXCR4 激动剂可能为治疗 AML 提供一种新的治疗方法。该项目是优化小分子 CXCR4 激动剂探针，并在体外和体内表征其针对 CXCR4 受体和 AML 的活性。激动剂和拮抗剂为我们提供了一套独特的分子工具来了解 CXCR4 受体药理学如何影响 AML 在目标 1 中，我们将使用合理的药物化学来优化我们的先导系列的效力和药物样特性，并结合计算机设计和强大的生物测试。我们将通过评估新的 CXCR4 调节剂在许多体外系统中的行为（包括钙动员、受体结合、受体内化、趋化性和信号传导）来表征 Aim 2 中的新 CXCR4 调节剂。目标 3 将使用白血病细胞系和原代人类肿瘤细胞以及体内使用 AML 异种移植模型来评估 CXCR4 调节对 AML 的影响。拟议的研究将产生新的分子探针来研究药理学。 CXCR4 并了解这一重要受体如何参与 AML。这些结果将为 AML 提供新的见解，并可能为治疗开发开辟新途径。