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

趋化因子受体CXCR4是一种GPCR，可转导其内源性配体CXCL12（基质细胞衍生因子-1，SDF-1）的信号。CXCL12-CXCR4系统最近被证明参与了几个问题疾病，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被确定为第二受体，用于T细胞系（X4-） HIV-1进入。其次，Muller等人报道了CXCL12-CXCR4系统可能决定乳腺癌细胞的转移目的地。近年来，该系统已被确认参与多种类型癌症的转移，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肿瘤，以及慢性淋巴细胞白血病b细胞和b前急性淋巴细胞白血病细胞的进展。第三，Nanki等人指出CXCL12和CXCR4的相互作用在RA滑膜T细胞聚集中起关键作用。因此，CXCR4被认为是克服上述疾病的重要治疗靶点。14聚肽，T140及其类似物，先前被发现是特异性CXCR4拮抗剂，其特征是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的药效团的了解，通过高效利用两个正交的环状五肽文库（构象文库和序列文库）发现了CXCR4拮抗剂FC131。我们已经开发了低分子量的CXCR4拮抗剂，包括FC131类似物，其中环肽环的结构调整和化学修饰进行了增加效力和减少肽特征。

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.