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

描述（由申请人提供）：总体目标是开发具有特异性和安全性的强效抗cxcr4药物。尽管CXCR4是干预多种疾病，特别是癌症转移的良好靶点，但目前临床上还没有安全的药物。转移是许多实体瘤类型的最终结果，也是癌症相关死亡的主要原因。在过去的十年中，学术界和工业界的研究小组越来越关注这一点，将其作为转移性疾病干预和延长生命的目标。迄今为止，许多靶分子已被解决，它们与转移相关的各种子步骤有机制联系，包括：1)在原发部位建立血管生成；(二)运动;Iii)转移细胞对特定器官的化学吸引、归巢和粘附；iv)转移性肿瘤生长和血管生成的建立。CXCR4/SDF-1相互作用，以及由此产生的细胞信号级联，最近被认为是最相关的靶标之一，因为它已被证明在上述所有四个步骤中发挥关键作用。我们已经发现了一组小分子CXCR4拮抗剂，目前正在对其特异性和效力进行评估。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是目前最先进的，它能有效结合CXCR4，从而阻断CXCR4/SDF-1信号通路。我们在体外和体内研究中证实WZ40通过抑制CXCR4/SDF-1相互作用抑制肿瘤转移。我们的基本假设是WZ40及其类似物是CXCR4/SDF-1相互作用的特异性抑制剂。具体目标是：1。设计和制备具有日益多样化的化学支架的改进抑制剂；2. 确定所选化合物对其他趋化因子受体的特异性；和3。根据血浆稳定性，口服有效性和体内有效性选择和发展合适的候选药物。该提案的预期结果是鉴定出能够通过阻断CXCR4功能来减轻体内肿瘤转移的小分子，同时展示足够的药代动力学和特异性特征，以推进人体临床评估。

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.