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，负责传递其内源性配体CXCL12(基质细胞衍生因子-1，SDF-1)的信号。CXCL12-CXCR4系统最近被证明与一些有问题的疾病有关，包括HIV感染、癌细胞转移、白血病细胞进展和类风湿关节炎(RA)：首先，CXCR4被确定为第二个受体，用于T细胞嗜性(X4-)HIV-1的进入。第二，穆勒等人。报道称，CXCL12-CXCR4系统可能决定了乳腺癌细胞的转移目的地。近年来，该系统被认为与多种癌症的转移有关，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。提示CXCL12和CXCR4之间的相互作用在RA滑膜中T细胞聚集过程中起关键作用。因此，CXCR4被认为是克服上述疾病的重要治疗靶点。T140及其类似物是CXCR4的特异性拮抗剂，主要有HIV进入抑制剂、抗肿瘤转移药、抗慢性淋巴细胞/急性淋巴细胞白血病药和抗RA药等。根据我们对T140的药效团的了解，通过有效地利用两个由构象文库和序列文库组成的正交环状五肽文库，发现了CXCR4拮抗剂，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，其中对环肽环进行了结构调整和化学修饰，以提高效力和降低多肽特性。

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.