Development of anti-CXCR4 compounds to block breast cancer metastasis

描述(申请人提供)：转移，即肿瘤细胞扩散和生长到远处器官部位，是癌症最具破坏性的属性，在乳腺癌的发病率和死亡率中起着重要作用。乳腺癌以一种刻板印象的模式转移，导致在淋巴、肺、肝脏和骨髓中发现病变。在关注CXC趋化因子受体-4(CXCR4)及其配体基质细胞衍生因子-1(SDF-1)的作用的同时，最近的转移研究进展表明，CXCR4/SDF-1在乳腺癌的器官选择性发展中也发挥着关键作用。具有讽刺意味的是，目前还没有专门针对转移过程的安全疗法。CXCR4/SDF-1的相互作用和由此产生的细胞信号级联已成为高度相关的靶点，因为它们在转移过程中扮演着多重角色，特别是归巢。AMD3100(MOZOBIL)是目前临床上唯一一种抗CXCR4的药物，已被批准作为干细胞动员剂。然而，长期使用可能会导致纤维化，因为骨髓间充质干细胞动员到肺和肝脏。我们开发了一类耐人寻味的新型嘧啶类胺类化合物，具有独特的部分抗CXCR4活性。这些化合物是有效的抗转移药物，在不动员干细胞或干扰CXCR4的其他功能的情况下，阻止癌细胞和肿瘤基质成分的归巢和募集。这是特别有价值的，因为CXCR4和SDF-1之间的相互作用对正常生理至关重要。小分子嘧啶胺为抗CXCR4药物提供了化学结构基础，这些药物预示着更安全的治疗方法，有可能长期消除对转移癌症的发展至关重要的CXCR4功能。其目的是开发一种口服可用、安全有效的药物来对抗CXCR4/SDF-1的长期影响，同时展示出值得推进到人类临床评估的药代动力学和特异性。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抗转移化合物；2)根据血浆稳定性、口服生物利用度和体内疗效选择和进展合适的候选药物；以及3)鉴定适合临床应用的候选药物。

DESCRIPTION (provided by applicant): Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute of cancer and plays a major role in the morbidity and mortality of breast cancer. Breast cancer metastasizes in a stereotypical pattern, resulting in lesions found in the lymph node, lung, liver and bone marrow. In parallel with hemopoietic stem cell homing, where attention has focused on the role of CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (SDF-1), recent advances in metastasis research suggest that here too CXCR4/SDF-1 play a critical role in the organ-selective development of breast cancer. Ironically, at present there are no safe therapies that specifically target the metastatic process. The CXCR4/SDF-1 interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression, especially homing. AMD3100 (Mozobil), the only anti-CXCR4 drug currently in the clinic, has been approved as a stem cell mobilizing agent. However, long-term use can result in fibrosis due to mobilization of mesenchymal stem cells to the lungs and liver. We have developed an intriguing novel class of pyrimidine amines with unique partial anti-CXCR4 activity. The compounds are effective anti- metastatic agents that block homing and recruitment of both cancerous cells and tumor stromal components without mobilizing stem cells or interfering with other functions of CXCR4. This is of particular merit because the interplay between CXCR4 and SDF-1 is critical for normal physiology. The small molecule pyrimidine amines offer a chemical structural foundation for anti-CXCR4 drugs that foretell safer therapeutics with potential for long-term elimination of CXCR4 functions critical for the development of metastatic cancer. The objective is to develop an orally available, safe and efficacious drug against the long-term effects of CXCR4/SDF-1, while demonstrating a pharmacokinetic and specificity profile to merit advancement into human clinical evaluation. The specific aims are: 1) Design and prepare improved anti-metastatic compounds with increasingly diverse chemical scaffolds; 2) Select and progress suitable candidates based on plasma stability, oral bioavailability and in vivo efficacy; and 3) Characterize suitable drug-candidates for advancement to the clinic.