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，可转导其内源配体 CXCL12（基质细胞衍生因子 1，SDF-1）的信号。 CXCL12-CXCR4 系统最近被证明与多种疑难疾病有关，包括 HIV 感染、癌细胞转移、白血病细胞进展和类风湿性关节炎 (RA)：首先，CXCR4 被确定为 T 细胞中使用的第二种受体线向性 (X4-) HIV-1 进入。其次，穆勒等人。报道称CXCL12-CXCR4系统可能决定乳腺癌细胞的转移目的地。最近，该系统已被认为参与多种癌症的转移，如胰腺癌、黑色素瘤、前列腺癌、肾癌、神经母细胞瘤、非霍奇金淋巴瘤、肺癌、卵巢癌、多发性骨髓瘤和恶性脑癌肿瘤，以及慢性淋巴细胞白血病 B 细胞和前 B 急性淋巴细胞白血病细胞的进展。第三，南基等人。表明 CXCL12 和 CXCR4 之间的相互作用在 RA 滑膜中 T 细胞积累中起着关键作用。因此，CXCR4被认为是克服上述疾病的重要治疗靶点。十四肽 T140 及其类似物先前被发现是特异性 CXCR4 拮抗剂，其特征为 HIV 进入抑制剂、抗癌转移剂、抗慢性淋巴细胞/急性淋巴细胞白血病剂和抗 RA 剂。基于我们对T140药效团的了解，通过有效利用由基于构象和基于序列的文库组成的两个正交环状五肽文库，发现了CXCR4拮抗剂，例如FC131。我们开发了低分子量 CXCR4 拮抗剂，包括 FC131 类似物，其中对环肽环进行结构调整和化学修饰，以提高效力并减少肽特征。