Truncated Actin-Targeting Macrolide Derivative Blocks Cancer Cell Motility and Invasion of Extracellular Matrix
Truncated Actin-Targeting Macrolide Derivative Blocks Cancer Cell Motility and Invasion of Extracellular Matrix
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DOI：
10.1021/jacs.0c12404
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发表时间：
2021-05-03
影响因子：
15
通讯作者：
Evans, P. Andrew
中科院分区：
文献类型：
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作者：
Pipaliya, Bhavin, V;Trofimova, Daria N.;Evans, P. Andrew
肿瘤转移是一个复杂的过程，肿瘤细胞高度移动，突破组织屏障，进入血液和淋巴系统，并作为循环肿瘤细胞扩散到全身。促成这些关键事件的主要细胞机制是肌动蛋白细胞骨架的重组。Mycalolide B （MycB）是一种靶向肌动蛋白的海洋大环内酯，在低纳摩尔剂量下可以抑制乳腺癌和卵巢癌细胞的增殖、迁移和侵袭。通过对MycB的肌动蛋白结合尾部区域（C24-C35）的结构-活性关系研究，我们发现了一个有效的截断衍生物，它可以抑制g -肌动蛋白的聚合，并通过结合肌动蛋白的倒钩端间隙切断f -肌动蛋白。这种微型MycB衍生物的生物学分析表明，它可以引起卵巢癌细胞中肌动蛋白细胞骨架的快速崩溃，并通过抑制侵入性细胞外基质（ECM）的降解来损害癌细胞的运动和侵袭。这些研究为开发以肌动蛋白为靶点的治疗药物来阻断癌症转移提供了必要的原理证明，并建立了一个可合成的易处理的倒刺末端结合药效团，可以通过添加靶向群来进一步改进药物的精准设计。
Cancer metastasis is a complex process involving highly motile tumor cells that breach tissue barriers, enter the bloodstream and lymphatic system, and disseminate throughout the body as circulating tumor cells. The primary cellular mechanism contributing to these critical events is the reorganization of the actin cytoskeleton. Mycalolide B (MycB) is an actin-targeting marine macrolide that can suppress proliferation, migration, and invasion of breast and ovarian cancer cells at low nanomolar doses. Through structure-activity relationship studies focused on the actin-binding tail region (C24-C35) of MycB, we identified a potent truncated derivative that inhibits polymerization of G-actin and severs F-actin by binding to actin's barbed end cleft. Biological analyses of this miniature MycB derivative demonstrate that it causes a rapid collapse of the actin cytoskeleton in ovarian cancer cells and impairs cancer cell motility and invasion of the extracellular matrix (ECM) by inhibiting invadopodia-mediated ECM degradation. These studies provide essential proof-of-principle for developing actin-targeting therapeutic agents to block cancer metastasis and establish a synthetically tractable barbed end-binding pharmacophore that can be further improved by adding targeting groups for precision drug design.