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

描述（由申请人提供）：总体目标是开发特异性和安全的强效抗CXCR 4药物。尽管CXCR 4是干预各种疾病，特别是癌症转移的良好靶点，但迄今为止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，并且是癌症相关死亡的主要原因。在过去的十年中，这已经吸引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。迄今为止，已经提出了许多靶分子，其在机制上与转移相关的各种子步骤相关联，包括：i）在原发部位建立血管生成; ii）运动; iii）转移性细胞对限定器官的化学吸引、归巢和粘附;以及iv）建立转移性肿瘤生长和血管生成。CXCR 4/SDF-1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此类靶标之一，因为它已被证明在上述所有四个步骤中发挥关键作用。已经发现了一组小分子CXCR 4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产新的类似物，以优化功效并扩大我们的结构范围。WZ 40是目前最先进的，它可以有效地与CXCR 4结合，从而阻断CXCR 4/SDF-1信号传导过程。我们通过在体外和体内研究中证明WZ 40通过抑制CXCR 4/SDF-1相互作用来抑制肿瘤转移来跟踪这一发现。我们的基本假设是WZ 40及其类似物是CXCR 4/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;以及3.根据血浆稳定性、口服利用度和体内疗效选择和发展合适的候选药物。该提案的预期结果是鉴定通过阻断CXCR 4功能在体内减弱肿瘤转移的小分子，同时证明足够的药代动力学和特异性特征，值得推进人类临床评价。

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.