Development of a unique small molecule modulator of CXCR4.
Development of a unique small molecule modulator of CXCR4.
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DOI：
10.1371/journal.pone.0034038
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shim H
中科院分区：
文献类型：
--
作者：
Liang Z;Zhan W;Zhu A;Yoon Y;Lin S;Sasaki M;Klapproth JM;Yang H;Grossniklaus HE;Xu J;Rojas M;Voll RJ;Goodman MM;Arrendale RF;Liu J;Yun CC;Snyder JP;Liotta DC;Shim H
转移，即肿瘤细胞向远处器官部位的扩散和生长，代表了最具破坏性的属性，并且在癌症的发病率和死亡率中发挥着重要作用。炎症对于恶性肿瘤的转化和生存至关重要。因此，阻断炎症有望成为有效的癌症治疗方法。在抗炎疗法中，趋化因子调节现已开始出现。 CXC 趋化因子受体 4 (CXCR4) 及其配体基质细胞衍生因子 1 (CXCL12) 相互作用以及由此产生的细胞信号级联反应已成为高度相关的靶标，因为它们在转移进展中发挥多效性作用。 CXCR4 的独特功能是促进肿瘤细胞归巢至远处器官部位的微环境。我们描述了 N,N'-(1,4-亚苯基双(亚甲基))二嘧啶-2-胺（命名为 MSX-122）的作用，这是一种新型小分子和部分 CXCR4 拮抗剂，其特性与任何其他报道的 CXCR4 拮抗剂完全不同，它是使用还原胺化反应在单个化学步骤中制备的。使用 18F 标记的 MSX-122 在结合亲和力测定和配体竞争测定中测试了其对 CXCR4 的特异性。该化合物的效力通过两种功能测定来确定：基质胶侵袭测定和 cAMP 调节。 MSX-122 在三种不同的炎症小鼠模型（包括实验性结肠炎、角叉菜胶诱导的爪水肿和博来霉素诱导的肺纤维化）和三种不同的转移动物模型（包括乳腺癌肺微转移、头颈癌肺转移和葡萄膜黑色素瘤肝微转移（据报道 CXCR4 在其中发挥关键作用））中评估了 MSX-122 的治疗潜力。我们开发了一种新型小分子MSX-122，它是一种部分CXCR4拮抗剂，无需动员干细胞，与其他报道的CXCR4拮抗剂相比，它可以更安全地长期阻断转移。
Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment. Among anti-inflammation therapies, chemokine modulation is now beginning to emerge from the pipeline. CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (CXCL12) interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression. The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites. We describe the actions of N,N′-(1,4-phenylenebis(methylene))dipyrimidin-2-amine (designated MSX-122), a novel small molecule and partial CXCR4 antagonist with properties quite unlike that of any other reported CXCR4 antagonists, which was prepared in a single chemical step using a reductive amination reaction. Its specificity toward CXCR4 was tested in a binding affinity assay and a ligand competition assay using 18F-labeled MSX-122. The potency of the compound was determined in two functional assays, Matrigel invasion assay and cAMP modulation. The therapeutic potential of MSX-122 was evaluated in three different murine models for inflammation including an experimental colitis, carrageenan induced paw edema, and bleomycin induced lung fibrosis and three different animal models for metastasis including breast cancer micrometastasis in lung, head and neck cancer metastasis in lung, and uveal melanoma micrometastasis in liver in which CXCR4 was reported to play crucial roles. We developed a novel small molecule, MSX-122, that is a partial CXCR4 antagonist without mobilizing stem cells, which can be safer for long-term blockade of metastasis than other reported CXCR4 antagonists.
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影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
影响因子：
120.1
作者：
De Clercq, E
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De Clercq, E
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Kajiyama, Hiroaki;Shibata, Kiyosumi;Kikkawa, Fumitaka
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Kikkawa, Fumitaka
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0.9
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