Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors

BEI SHAN; JULIO C. MEDINA; EDIT SANTHA; WALTER P. FRANKMOELLE; TING-C. CHOU; ROBERT M. LEARNED; MATHEW R. NARBUT; DEAN STOTT; PENGGUANG WU; JUAN C. JAEN; TERRY ROSEN; PIETER B. M. W. M. TIMMERMANS; HOLGER BECKMANN

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Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors

机译：T138067是一种对多药耐药肿瘤具有体内功效的抗肿瘤药，对β-微管蛋白残基Cys-239进行选择性，共价修饰

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Microtubules are linear polymers of α- and β-tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the β_1, β_2, and β_4 isotypes of β-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.

机译：微管是α-和β-微管蛋白异二聚体的线性聚合物，是有丝分裂纺锤体的主要成分，对有丝分裂过程中的染色体分离至关重要。在这里，我们描述了一种合成化合物2-氟-1-甲氧基-4-五氟苯基磺酰胺基苯（T138067），它在保守的半胱氨酸残基上共价和选择性地修饰β-微管蛋白的β_1，β_2和β_4同种型，从而破坏微管聚合。暴露于T138067的细胞形状发生改变，表明细胞骨架瓦解，并显示染色体倍性增加。随后，这些细胞发生凋亡。此外，T138067对肿瘤细胞系表现出细胞毒性，该肿瘤细胞系对长春碱，紫杉醇，阿霉素和放线菌素D具有实质性耐药性。T138067在抑制无胸腺裸鼠中敏感和多药耐药的人肿瘤异种移植物的生长方面同样有效。这些观察结果提示，T138067在临床上可用于治疗多药耐药性肿瘤。

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《Proceedings of the National Academy of Sciences of the United States of America》 |1999年第10期|p.5686-5691|共6页
作者
BEI SHAN; JULIO C. MEDINA; EDIT SANTHA; WALTER P. FRANKMOELLE; TING-C. CHOU; ROBERT M. LEARNED; MATHEW R. NARBUT; DEAN STOTT; PENGGUANG WU; JUAN C. JAEN; TERRY ROSEN; PIETER B. M. W. M. TIMMERMANS; HOLGER BECKMANN;
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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类自然科学总论;
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1. Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors [J] . BEI SHAN, JULOI C.MEDINA, EDIT SANTHA Proceedings of the National Academy of Sciences of the United States of America . 1999,第10期

机译：T138067是一种对多药耐药肿瘤具有体内功效的抗肿瘤药，选择性，共价修饰β-微管蛋白残基Cys-239
2. In Vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents [J] . Cui Mu-Tian, Jiang Li, Goto Masuo, Journal of Medicinal Chemistry . 2017,第13期

机译：抗肿瘤铅7-甲氧基-4-（2-甲基喹唑啉-4-基）-3,4-二氢喹啉-2（1H）的体内和机械研究 - IONO和其改性为小型类小蛋白结合肿瘤血管扰乱代理人
3. BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy. [J] . Kremmidiotis G, Leske AF, Lavranos TC, Molecular cancer therapeutics . 2010,第6期

机译：BNC105：一种新型微管蛋白聚合抑制剂，可选择性破坏肿瘤血管并显示单药抗肿瘤功效。
4. Mass Spectrometry Analysis of Antitumor Steroidal Lactone Withaferin A Covalent Binding to Cysteine-303 of β-Tubulin in Human Breast Cancer Cells [C] . Guy T. Uechi, Marie Lue Antony, Eun-Ryeong Hahm, ASMS Conference on Mass Spectrometry and Allied Topics . 2014

机译：抗肿瘤甾体内酯的质谱分析与人乳腺癌细胞中β-微蛋白的半胱氨酸-303共价结合
5. The antitumor agent ecteinascidin 743 (Et 743): Characterization of its covalent DNA adducts and its effect on DNA repair mechanisms. [D] . Foote, Maha Zewail. 2000

机译：抗肿瘤药物ecteinascidin 743（Et 743）：其共价DNA加合物的特征及其对DNA修复机制的影响。
6. Selective covalent modification of β-tubulin residue Cys-239 by T138067 an antitumor agent with in vivo efficacy against multidrug-resistant tumors [O] . Bei Shan, Julio C. Medina, Edit Santha, 1999

机译：T138067是一种对多药耐药肿瘤具有体内功效的抗肿瘤药对β-微管蛋白残基Cys-239进行选择性共价修饰
7. In Vivo and Mechanistic Studies on Antitumor Lead 7Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents [O] . -1

机译：在抗肿瘤铅7甲氧基-4-（2-甲基喹唑啉-4-基）-3,4-二氢喹啉-2-2（1H）的体内和机械研究，其改性为一种小型类胰蛋白结合肿瘤血管破坏剂

Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors

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