The legumain protease-activated auristatin prodrugs suppress tumor growth and metastasis without toxicity.
The legumain protease-activated auristatin prodrugs suppress tumor growth and metastasis without toxicity.
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DOI：
10.1002/cmdc.201000478
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发表时间：
2011-01-03
期刊：
影响因子：
3.4
通讯作者：
Sinha, Subhash C.
中科院分区：
文献类型：
--
作者：
Bajjuri, Krishna Mohan;Liu, Yuan;Liu, Cheng;Sinha, Subhash C.
天然存在的抗有丝分裂五肽dolastatin 10(1，图1)[1]及其合成类似物auristatin E (AE, 2)[2]对许多人类癌细胞系具有亚纳摩尔的细胞毒性，其效力比目前临床上使用的许多药物，包括紫杉醇和阿霉素，分别高出一百到一千倍。这些五肽的作用机制与紫杉醇相似，但其作用过程似乎是相反的；也就是说，抗甾肽和抗甾肽抑制微管蛋白聚合，而紫杉醇促进微管聚合并稳定微管最后，dolastatin或auristins和紫杉醇都抑制细胞增殖。此外，耳垢可以作为血管破坏剂，破坏已建立的肿瘤血管，因此可能比紫杉醇在体内产生更明显的效果尽管如此，抗炎药和抗炎药的治疗效果很差，因为它们也会对正常细胞产生非选择性毒性Seattle Genetics率先将auristatin选择性递送至肿瘤细胞，将其进一步修饰为合适的类似物，包括didesmethylauristatin E （DDAE, 3）和monom甲基lauristatin E (MMAE, 4)，并通过连接物将其偶联到Fc区域的肿瘤靶向抗体（Ab）结合物在肿瘤细胞中被摄取后，通过溶酶体蛋白酶催化的连接物水解释放游离药物。许多这样的auristatin-Ab缀合物在肿瘤模型中显示出非常高的疗效，并且一些缀合物正在临床试验中用于治疗各种癌症我们对这类分子很感兴趣，因为它们也可以为我们正在进行的前体药物[8]及其与编程抗体（progAbs）的偶联物的开发提供支持首先，我们制备并评估了一系列AE(2)类似物，并将其与之前描述的类似物DDAE和MMAE进行了细胞毒性比较。对结果的检查显示，新的耳抑素类似物是非常有效的，但它们的细胞毒性不如化合物1-4。因此，我们以MMAE和DDAE为研究对象，制备并评价了它们经过肿瘤相关蛋白酶催化活化的前药。在此，我们报告我们的初步研究结果
Naturally occurring antimitotic pentapeptide dolastatin 10 (1, Figure 1)[1] and its synthetic analogue auristatin E (AE, 2)[2] possess subnanomolar cytotoxicity against many human cancer cell lines and are over a hundred-to a thousand-times more potent than many pharmaceuticals, including taxol and doxorubicin, respectively, which are currently used in clinic. These pentapeptides have mechanism of actions similar to that of taxol, but through processes that appear opposing to each other; that is, dolastatins and auristatins inhibit tubulin polymerization, whereas taxol promotes it and stabilizes the microtubules.[3] In the end, both dolastatins or auristatins and taxol inhibit cell proliferation. Additionally, auristatins function as the vascular disrupting agents and damage the established tumor vessels, thereby likely causing a more pronounced effect than taxol in vivo.[4] Nonetheless, the therapeutic efficacies of the auristatins and dolastatins are poor as they also cause nonselective toxicity to normal cells.[5] Seattle Genetics has pioneered the selective delivery of auristatins to tumor cells by further modifying them to suitable analogues, including didesmethylauristatin E (DDAE, 3) and monomethylauristatin E (MMAE, 4), and conjugating them to tumor-targeting antibodies (Ab) in the Fc region through a linker.[6] Upon uptake of the conjugates in tumor cells, free drugs are released by lysosomal protease-catalyzed hydrolysis of the linker. Many such auristatin–Ab conjugates have shown very high efficacy in tumor models, and several conjugates are in clinical trials for the treatment of various cancers.[7] We are interested in this class of molecules as they could also feed our ongoing program in the development of prodrugs [8] and their conjugates to the programmed Abs (progAbs).[9] First, we prepared and evaluated a series of AE (2) analogues and compared their cytotoxicity to the previously described analogues, DDAE and MMAE. An examination of the results revealed that new auristatin analogues were highly potent, but they were not as cytotoxic as compounds 1–4. Therefore, we focused on MMAE and DDAE, and prepared and evaluated their prodrugs, which undergo tumor-associated protease-catalyzed activation. Herein, we report the results of our preliminary study
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影响因子：
1.8
作者：
Li, Lian-Sheng;Sinha, Subhash C.
通讯作者：
Sinha, Subhash C.
影响因子：
7.3
作者：
Gotz, Marion G.;James, Karen Ellis;Powers, James C.
通讯作者：
Powers, James C.
影响因子：
2.7
作者：
Goswami, Rajib Kumar;Huang, Zheng-Zheng;Sinha, Subhash C.
通讯作者：
Sinha, Subhash C.
影响因子：
3.5
作者：
Morita, Yoshikata;Araki, Hisazumi;Ohkubo, Iwao
通讯作者：
Ohkubo, Iwao
DOI：
10.1073/pnas.0700223104
发表时间：
2007-03-27
影响因子：
11.1
作者：
Abraham, Sunny;Guo, Fang;Sinha, Subhash C.
通讯作者：
Sinha, Subhash C.