MPC-6827: A small-molecule inhibitor of microtubule formation that is not a substrate for multidrug resistance pumps
MPC-6827: A small-molecule inhibitor of microtubule formation that is not a substrate for multidrug resistance pumps
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DOI：
10.1158/0008-5472.can-07-0127
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Pleiman, Christopher M.
中科院分区：
文献类型：
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作者：
Kasibhatla, Shailaja;Baichwal, Vijay;Pleiman, Christopher M.
从基于细胞的筛选试验中鉴定了一系列新的4-芳氨基喹唑啉类化合物作为有效的凋亡诱导剂。通过结构-活性关系研究，发现MPC-6827及其紧密结构类似物MPI-0441138是促凋亡分子和有丝分裂抑制剂，在多种肿瘤细胞系中在低纳摩尔浓度下具有效力。发现MPC-6827的光亲和性和放射性标记类似物结合55-kDa蛋白，并且这种结合被NIPC-6827、紫杉醇和秋水仙碱竞争，但不被长春碱竞争。MPC-6827在体外有效抑制微管蛋白的聚合，与秋水仙素竞争结合，并破坏多种肿瘤细胞系中微管的形成，这些肿瘤细胞系共同显示分子靶标为微管蛋白。用MPC-6827处理MCF-7乳腺癌或Jurkat白血病细胞导致明显的G（2）-M细胞周期停滞，随后发生凋亡。细胞凋亡，如通过末端脱氧核糖核苷酸转移酶介导的dUTP缺口末端标记法测定的，之前的线粒体膜电位的损失，细胞色素c从线粒体易位到细胞核，caspase-3的激活，和裂解的聚（ADP-核糖）聚合酶。MPC-6827在几种癌细胞系的体外生长抑制试验中具有等效性，无论多药耐药ABC转运蛋白MDR-1（Pgp-1）、MRP-1和BCRP-1的表达水平如何。在B16-F1同种异体移植物和OVCAR-3、MIAPaCa-2、MCF-7、HT-29、MDA-MB-435和MX-1异种移植物中，MPC-6827观察到统计学显著的肿瘤生长抑制。这些研究表明，MPC-6827是一种微管破坏剂，具有有效和广谱的体外和体内细胞毒性活性，因此，MPC-6827是一种有前途的候选药物，可用于开发多种癌症类型的新型治疗药物。
A novel series of 4-arylamino-quinazolines were identified from a cell-based screening assay as potent apoptosis inducers. Through structure-activity relationship studies, MPC-6827 and its close structural analogue, MPI-0441138, were discovered as proapoptotic molecules and mitotic inhibitors with potencies at low nanomolar concentrations in multiple tumor cell lines. Photoaffinity and radiolabeled analogues of MPC-6827 were found to bind a 55-kDa protein, and this binding was competed by NIPC-6827, paclitaxel, and colchicine, but not vinblastine. MPC-6827 effectively inhibited the polymerization of tubulin in vitro, competed with colchicine binding, and disrupted the formation of microtubules in a variety of tumor cell lines, which together showed the molecular target as tubulin. Treatment of MCF-7 breast carcinoma or jurkat leukemia cells with MPC-6827 led to pronounced G(2)-M cell cycle arrest followed by apoptosis. Apoptosis, as determined by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay, was preceded by loss of mitochondrial membrane potential, cytochrome c translocation from mitochondria to nuclei, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. MPC-6827 was equipotent in an in vitro growth inhibition assay in several cancer cell lines regardless of the expression levels of the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. In B16-F1 allografts and in OVCAR-3, MIAPaCa-2, MCF-7, HT-29, MDA-MB-435, and MX-1 xenografts, statistically significant tumor growth inhibition was observed with MPC-6827. These studies show that MPC-6827 is a microtubule-disrupting agent with potent and broad-spectrum in vitro and in vivo cytotoxic activities and, therefore, MPC-6827 is a promising candidate for development as a novel therapeutic for multiple cancer types.