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

• 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
• 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

 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，如HIV感染、炎症、肿瘤发生、干细胞迁移和自身免疫性疾病。尽管CXCR4受体及其独特的配体SDF-1已被广泛研究，但所有SDF-1/CXCR4轴的小分子调节剂都是拮抗剂。由于缺乏可用的小分子激动剂，探索 CXCR4 生物学的能力存在巨大差距。使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，并证明了它们在各种生物环境中的独特行为。值得注意的是，我们的小分子会引起 CXCR4 受体的内化、强烈的趋化反应以及肿瘤细胞系的化学敏化。这些小分子激动剂和结构相关拮抗剂的开发将为研究 CXCR4 受体的功能及其与疾病过程的关系提供独特而强大的手段。急性髓系白血病 (AML) 是一组髓系白血病，如果不及时治疗，病程非常具有侵袭性和致命性。骨髓 (BM) 微环境对化疗具有重要的保护作用，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中发挥着关键作用，其表达已被证明与许多癌症的预后呈负相关。我们的主要激动剂显着增强了多种白血病细胞系对多种化疗的化疗敏感性，表明 CXCR4 激动剂可能为 AML 的治疗提供一种新的治疗方法。该项目的总体目标是优化小分子 CXCR4 激动剂探针，并表征其在体外和体内针对 CXCR4 受体和 AML 的活性。我们独特的小分子 CXCR4 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类药特性，将计算机设计和稳健的生物测试纳入迭代过程。我们将通过评估其针对许多体外系统的行为（包括钙动员、受体结合、受体内化、趋化性和通过各种途径的信号传导）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使用患者来源的 AML 异种移植模型在体内评估 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 CXCR4 的药理学并了解这种重要受体如何参与 AML。这些结果将为 AML 提供新的见解，并有可能为治疗开发开辟新的途径。