Development of anti-CXCR4 compounds to block breast cancer metastasis

开发抗 CXCR4 化合物来阻止乳腺癌转移

基本信息

批准号：
9022432
负责人：
HYUNSUK SHIM
金额：
$ 32.07万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-09 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9022432
关键词：
AMD3100 Academia Address Affinity Amines Animal Model Attention Attenuated Binding Biological Assay Biological Availability Bone Marrow Breast cancer metastasis CXC Chemokines Cancer Etiology Cancerous Carrageenan Cells Cessation of life Chemicals Clinic Clinical Cyclic AMP Dependency Development Disease Disseminated Malignant Neoplasm Distant Dose Drug Kinetics Edema Endothelium Fibrosis Foundations Growth High Pressure Liquid Chromatography Homing Human In Vitro Industry Inflammation Intervention Lead Lesion Life Extension Ligands Liver Long-Term Effects Lung Malignant Neoplasms Maps Marketing Matrigel Invasion Assay Mesenchymal Stem Cells Modeling Morbidity - disease rate Neoplasm Metastasis Oral Organ Outcome Pattern Pharmaceutical Preparations Physiology Plasma Play Process Pyrimidine Quantitative Structure-Activity Relationship Research Role Signal Transduction Site Solid Neoplasm Specificity Stem cells Stromal Cell-Derived Factor 1 Stromal Neoplasm Structure Testing Therapeutic Time Tissues Toxic effect Transgenic Organisms Transplantation analog base chemokine receptor design drug candidate improved in vivo in vivo Model inhibitor/antagonist lymph nodes macrophage malignant breast neoplasm matrigel metabolic abnormality assessment metastatic process mortality mouse model nanomolar neoplastic cell novel programs research clinical testing scaffold screening small molecule tumor tumor microenvironment

项目摘要

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.

描述（由申请人提供）：转移，肿瘤细胞向远处器官部位的扩散和生长代表了癌症的最具破坏性属性，并且在乳腺癌的发病率和死亡率中起着重要作用。乳腺癌以定型模式转移，导致淋巴结，肺，肝和骨髓的病变。与血压干细胞的同时，注意力集中在CXC趋化因子受体-4（CXCR4）及其配体间质细胞衍生因子1（SDF-1）的作用上，转移研究的最新进展表明，在这里，CXCR4/SDF-1在乳腺癌的乳腺癌发育中也起着至关重要的作用。具有讽刺意味的是，目前尚无针对转移过程的安全疗法。 CXCR4/SDF-1相互作用和所得的细胞信号级联反应已成为高度相关的靶标，因为它们在转移性进程中扮演了多效性角色，尤其是归因。 AMD3100（Mozobil）是目前诊所中唯一的抗CXCR4药物，已被批准为干细胞动员剂。然而，由于间充质干细胞向肺和肝脏动员，长期使用可能导致纤维化。我们开发了一种具有独特的部分抗CXCR4活性的有趣的新型嘧啶胺类。这些化合物是有效的抗转移剂，可阻止癌细胞和肿瘤基质成分的归巢和募集，而无需动员干细胞或干扰CXCR4的其他功能。这是特别值得的，因为CXCR4和SDF-1之间的相互作用对于正常生理学至关重要。小分子嘧啶胺为抗CXCR4药物提供了化学结构基础，该药物预测了更安全的疗法，其长期消除CXCR4可能对转移性癌症的发展至关重要。目的是开发一种针对CXCR4/SDF-1的长期影响的口服，安全有效的药物，同时证明了药代动力学和特异性特征，以提高人类临床评估。具体目的是：1）设计和制备具有越来越多样化的化学支架的改进的抗转移化合物； 2）基于血浆稳定性，口服生物利用度和体内功效选择合适的候选者； 3）表征合适的药物糖化物以促进诊所的发展。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A benzenesulfonamide derivative as a novel PET radioligand for CXCR4.

苯磺酰胺衍生物作为 CXCR4 的新型 PET 放射性配体。

DOI：
10.1016/j.bmc.2019.115240
发表时间：
2020
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Oum,YoonHyeun;Shetty,Dinesh;Yoon,Younghyoun;Liang,Zhongxing;Voll,RonaldJ;Goodman,MarkM;Shim,Hyunsuk
通讯作者：
Shim,Hyunsuk

Eliminating the heart from the curcumin molecule: monocarbonyl curcumin mimics (MACs).