A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors
A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors
复制标题
一种新型微管抑制剂克服肿瘤的多药耐药性
DOI：
10.1158/0008-5472.can-18-0455
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发表时间：
2018-10-15
期刊：
影响因子：
11.2
通讯作者：
Ren, Ruibao
中科院分区：
文献类型：
--
作者：
Ning, Nannan;Yu, Yamei;Ren, Ruibao
微管抑制剂作为化疗药物被广泛用于癌症治疗。然而，癌症中多药耐药性（MDR）的产生是微管抑制剂在临床应用中的一大挑战。通过对致癌RAS转化细胞进行高通量药物筛选，我们鉴定出一种先导杂芳基酰胺化合物，它能阻断细胞增殖。构效关系分析表明，这一系列骨架结构（以MP - HJ - 1b为代表）是肿瘤细胞生长的强效抑制剂。MP - HJ - 1b对1000多种来自不同组织的人类癌细胞系均有活性。该化合物可使微管解聚并影响纺锤体形成。它还能在体外和体内诱导微管形成钉状构象，这与典型的微管调节剂不同。结构分析显示，这一系列化合物结合在微管蛋白二聚体内部界面的秋水仙碱结合口袋处，尽管大部分结合位点与秋水仙碱的结合位点并不重叠。MP - HJ - 1b在体外和体内均展现出良好的克服肿瘤多药耐药性的药理特性。综上所述，我们的数据揭示了以MP - HJ - 1b为代表的一种新型骨架结构，可开发成为针对具有多药耐药性肿瘤的癌症治疗药物。
意义：紫杉醇是一种广泛用于多种癌症患者的化疗药物。然而，对紫杉醇的耐药性是一个难题。本研究描述了一类新型微管抑制剂，其具有绕过多种肿瘤细胞系多药耐药性的能力。（C）2018美国癌症研究协会。
Microtubule inhibitors as chemotherapeutic drugs are widely used for cancer treatment. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in their clinical implementation. From a high-throughput drug screen using cells transformed by oncogenic RAS, we identify a lead heteroaryl amide compound that blocks cell proliferation. Analysis of the structure-activity relationship indicated that this series of scaffolds (exemplified by MP-HJ-1b) represents a potent inhibitor of tumor cell growth. MP-HJ-1b showed activities against a panel of more than 1,000 human cancer cell lines with a wide variety of tissue origins. This compound depolymerized microtubules and affected spindle formation. It also induced the spike-like conformation of microtubules in vitro and in vivo, which is different from typical microtubule modulators. Structural analysis revealed that this series of compounds bound the colchicine pocket at the intradimer interface, although mostly not overlapping with colchicine binding. MP-HJ-1b displayed favorable pharmacological properties for overcoming tumor MDR, both in vitro and in vivo. Taken together, our data reveal a novel scaffold represented by MP-HJ-1b that can be developed as a cancer therapeutic against tumors with MDR.Significance: Paclitaxel is a widely used chemotherapeutic drug in patients with multiple types of cancer. However, resistance to paclitaxel is a challenge. This study describes a novel class of microtubule inhibitors with the ability to circumvent multidrug resistance across multiple tumor cell lines. (C) 2018 AACR.