Development of anti-CXCR4 compounds as anti-metastatic, angiogenic drug

开发抗 CXCR4 化合物作为抗转移、血管生成药物

• 批准号: 7430463
• 负责人: HYUNSUK SHIM
• 金额: $ 26.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430463
• 关键词: AMD3100; Academia; Address; Adhesions; Affinity; Attention; Attenuated; Binding; Biological Assay; CXCR4 gene; Calcium-Sensing Receptors; Cancer Etiology; Cell Line; Cells; Cessation of life; Chemicals; Clinic; Computer software; Dependency; Development; Disease; Dose; Drug Kinetics; Experimental Animal Model; Head and neck structure; High Pressure Liquid Chromatography; Homing; Human; In Vitro; Industry; Intervention; Lead; Life Extension; Link; Locomotion; Maps; Marketing; Modeling; Neoplasm Metastasis; Numbers; Oral; Organ; Outcome; Pharmaceutical Preparations; Plasma; Play; Process; Research; Research Personnel; Role; Screening procedure; Signal Transduction; Site; Solid Neoplasm; Specificity; Testing; Toxic effect; analog; angiogenesis; antiangiogenesis therapy; base; chemokine receptor; computerized data processing; design; improved; in vivo; in vivo Model; inhibitor/antagonist; matrigel; metabolic abnormality assessment; metastatic process; mutant; pre-clinical; predictive modeling; programs; release of sequestered calcium ion into cytoplasm; research clinical testing; scaffold; small molecule; tumor; tumor growth

DESCRIPTION (provided by applicant): The overall objective is to develop potent anti-CXCR4 drugs that are specific and safe. Even though CXCR4 is a good target for intervening various diseases, especially, cancer metastasis, there is no safe drug in the clinic until now. Metastasis is an end result for many solid tumor types and is the leading cause of cancer related deaths. This has attracted an increasing amount of attention from research groups over the last decade in both academia and industry, as a target for metastatic disease intervention and life extension. To date, a number of target molecules have been addressed that are linked mechanistically to the various sub- steps associated with metastasis including: i) establishment of angiogenesis at the primary site; ii) locomotion; iii) chemoattraction, homing, and adhesion of the metastatic cells to the defined organs; and iv) establishment of metastatic tumor growth and angiogenesis. The CXCR4/SDF-1 interaction, and the resulting cell signaling cascade, has recently emerged as one of the most relevant such targets as it has been shown to play a key role in all four steps outlined above. A set of small molecule CXCR4 antagonists has been discovered and we are currently in the process of evaluating specificity and potency. We are simultaneously designing and generating new analogs to optimize efficacy as well as expand our structural scope. WZ40 is currently the most advanced, which potently bind to CXCR4, thus, blocking the CXCR4/SDF-1 signaling process. We have followed this discovery by demonstrating that WZ40 inhibits tumor metastasis by inhibiting the CXCR4/SDF-1 interaction in both in vitro and in vivo studies. Our underlying hypothesis is that WZ40 and its analogs are specific inhibitors of CXCR4/SDF-1 interaction. The specific aims are: 1. Design and prepare improved inhibitors with increasingly diverse chemical scaffolds; 2. Determine the Specificity of selected compounds against other chemokine receptors; and 3. Select and progress suitable candidates based on plasma stability, oral availability, and in vivo efficacy. The intended outcome of this proposal is the identification of small molecules that will attenuate tumor metastasis in vivo by blocking CXCR4 function whilst demonstrating a sufficient pharmacokinetic and specificity profile to merit advancement into human clinical evaluation.

描述（由申请人提供）：总体目标是开发特定且安全的有效抗CXCR4药物。即使CXCR4是干预各种疾病的好目标，尤其是癌症转移，但迄今为止，诊所还没有安全的药物。转移是许多实体瘤类型的最终结果，并且是癌症相关死亡的主要原因。在过去的十年中，研究小组在学术界和工业中都引起了越来越多的关注，这是转移性疾病干预和延长生命的目标。迄今为止，已经解决了许多靶分子与转移相关的各种子步骤链接，包括：i）在主要部位建立血管生成； ii）运动； iii）转移细胞对定义的器官的趋化，归巢和粘附； iv）建立转移性肿瘤生长和血管生成。 CXCR4/SDF-1相互作用以及所得的细胞信号级联反应最近已成为最相关的目标之一，因为它已被证明在上面概述的所有四个步骤中都起着关键作用。已经发现了一组小分子CXCR4拮抗剂，我们目前正在评估特异性和效力。我们正在同时设计和生成新的类似物，以优化功效并扩大我们的结构范围。 WZ40当前是最先进的，它有效与CXCR4结合，因此阻止了CXCR4/SDF-1信号传导过程。我们遵循了这一发现，证明WZ40通过在体外和体内研究中抑制CXCR4/SDF-1相互作用来抑制肿瘤转移。我们的基本假设是WZ40及其类似物是CXCR4/SDF-1相互作用的特定抑制剂。具体目的是：1。设计和准备改进的化学脚手架的抑制剂； 2。确定所选化合物对其他趋化因子受体的特异性； 3。根据血浆稳定性，口服可用性以及体内功效选择和进步合适的候选者。该提案的预期结果是鉴定出小分子，通过阻止CXCR4功能来减轻体内肿瘤转移，同时证明了足够的药代动力学和特异性特征，以提高人类临床评估。