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

描述(由申请人提供)：总体目标是开发有效的抗CXCR4药物，这些药物是特异的和安全的。尽管CXCR4是干预多种疾病，特别是肿瘤转移的良好靶点，但到目前为止，临床上还没有安全的药物。转移是许多实体肿瘤类型的最终结果，也是癌症相关死亡的主要原因。在过去的十年里，这引起了学术界和工业界研究小组越来越多的关注，作为转移性疾病干预和延长生命的目标。到目前为止，许多靶分子已经被解决，这些分子与与转移相关的各个子步骤机械地联系在一起，包括：i)在原发部位建立血管生成；ii)运动；iii)转移细胞与特定器官的化学吸引、归巢和黏附；以及iv)建立转移瘤生长和血管生成。CXCR4/SDF-1的相互作用以及由此产生的细胞信号级联，最近已成为最相关的目标之一，因为它已被证明在上述所有四个步骤中发挥关键作用。一组小分子CXCR4拮抗剂已经被发现，我们目前正在评估特异性和有效性。我们同时设计和生成新的类似物，以优化疗效并扩大我们的结构范围。WZ40是目前最先进的，它能有效地与CXCR4结合，从而阻断CXCR4/SDF-1信号转导过程。我们遵循这一发现，在体外和体内研究中证明了WZ40通过抑制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相互作用的特异性抑制剂。具体的目标是：1.设计和制备具有日益多样化的化学支架的改进的抑制剂；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、口服利用度和体内疗效选择和进展合适的候选药物。这项建议的预期结果是鉴定小分子，通过阻断CXCR4功能来减少体内肿瘤转移，同时展示足够的药代动力学和特异性，值得进入人类临床评估。

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.