Shan B, Medina J C, Santha E, Frankmoelle W P, Chou T C, Learned R M, Narbut M R, Stott D, Wu P, Jaen J C, Rosen T, Timmermans P B, Beckmann H
Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA.
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5686-91. doi: 10.1073/pnas.96.10.5686.
Microtubules are linear polymers of alpha- and beta-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 beta1, beta2, and beta4 isotypes of beta-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.
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，而有丝分裂纺锤体对于有丝分裂期间染色体的分离至关重要。在此，我们描述了一种合成化合物，2-氟-1-甲氧基-4-五氟苯磺酰胺苯（T138067），它在一个保守的半胱氨酸残基处共价且选择性地修饰β-微管蛋白的β1、β2和β4亚型，从而破坏微管聚合。暴露于T138067的细胞形状发生改变，表明细胞骨架塌陷，并显示染色体倍性增加。随后，这些细胞发生凋亡。此外，T138067对显示出对长春碱、紫杉醇、阿霉素和放线菌素D具有显著抗性的肿瘤细胞系表现出细胞毒性。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生长方面同样有效。这些观察结果表明，T138067在临床上可能对多药耐药肿瘤的治疗有用。
