DEVELOPMENT OF CXCR4 ANTAGONISTS TARGETED TO ANTI-CANCER-METASTATIC AGENTS AND ANTI-HIV AGENTS

开发针对抗癌转移剂和抗 HIV 剂的 CXCR4 拮抗剂

基本信息

批准号：
15590099
负责人：
TAMAMURA Hirokazu
金额：
$ 2.18万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590099/
关键词：
chemokine receptor CXCR4 antagonist HIV infection cancer metastasis leukemia rheumatoid arthritis T140 cyclic peptide 癌転移抑制剤低分子化膵臓癌乳癌

项目摘要

The chemokine receptor, CXCR4, is a GPCR that transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12-CXCR4 system has recently been proven to be involved in several problematic diseases, including HIV infection, cancer cell metastasis, leukemia cell progression and rheumatoid arthritis (RA) : First, CXCR4 was identified as a second receptor that is utilized in T cell line-tropic (X4-) HIV-1 entry. Second, Muller et al. reported that the CXCL12-CXCR4 system might determine the metastatic destination of breast cancer cells. Recently, this system has been recognized to be involved in the metastasis of several types of cancers, such as pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, multiple myeloma and malignant brain tumor, as well as in the progression of chronic lymphocytic leukemia B-cells and pre-B acute lymphoblastic leukemia cells. Third, Nanki et al. indicated that the interaction between CXCL12 and CXCR4 plays a critical role in T cell accumulation in the RA synovium. Thus, CXCR4 is thought to be an important therapeutic target to overcome the above diseases. Fourteen-mer peptides, T140 and its analogs, were previously found to be specific CXCR4 antagonists that were characterized as HIV entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents. Based on our knowledge of pharmacophores of T140, CXCR4 antagonists, such as FC131, were found by the efficient utilization of two orthogonal cyclic pentapeptide libraries consisting of conformation-based and sequence-based libraries. We have developed low molecular weight CXCR4 antagonists including FC131 analogs, in which structural tuning of the cyclic peptide ring and chemical modifications were performed for an increase in potency and a reduction of the peptide charcter.

趋化因子受体CXCR4是一种GPCR，可传递其内源配体CXCL12（基质细胞衍生的因子-1，SDF-1）的信号。 CXCL12-CXCR4系统最近已被证明参与了几种有问题的疾病，包括HIV感染，癌细胞转移，白血病细胞进展和类风湿关节炎（RA）：首先，CXCR4被确定为第二种在T细胞系线特性（X4--）HIV-1中使用的第二受体。其次，Muller等。报道说CXCL12-CXCR4系统可能决定乳腺癌细胞的转移性目的地。最近，该系统已被认为参与了几种类型的癌症的转移，例如胰腺癌，黑色素瘤，前列腺癌，肾癌，神经母细胞瘤，非霍奇金的淋巴瘤，肺癌，肺癌，卵巢癌，卵巢癌，多发性骨髓瘤和恶性脑肿瘤，以及预先培训的前进症状症状症状症状症状。淋巴细胞白血病细胞。第三，Nanki等。表明CXCL12和CXCR4之间的相互作用在RA滑膜中T细胞积累中起关键作用。因此，CXCR4被认为是克服上述疾病的重要治疗靶标。先前发现14种-Mer肽T140及其类似物是特定的CXCR4拮抗剂，这些拮抗剂被描述为HIV进入抑制剂，抗癌剂，抗癌剂，抗chrononic淋巴细胞/急性淋巴细胞淋巴细胞淋巴细胞性白血病药物和抗RA剂。根据我们对T140药算算术的了解，通过有效利用两个正交环状五肽文库（由基于构象和基于序列的文库组成的正交环状五肽文库），发现了CXCR4拮抗剂（例如FC131）。我们已经开发了包括FC131类似物在内的低分子量CXCR4拮抗剂，其中进行了环状肽环的结构调整，并进行了化学修饰，以增加效力和肽电荷降低。