Rational design of the microtubule-targeting anti-breast cancer drug EM015
Rational design of the microtubule-targeting anti-breast cancer drug EM015
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DOI：
10.1158/0008-5472.can-05-2962
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Joshi, HC
中科院分区：
文献类型：
--
作者：
Aneja, R;Lopus, M;Joshi, HC
我们研究了诺斯卡品与微管蛋白的电子对接，结合表面电荷，π-π，货车德瓦尔斯和氢键相互作用的计算，合理地设计了一个新的化合物，EM 015。这种微管蛋白结合半合成化合物是一种选择性和有效的抗乳腺癌药物，与我们的创始化合物（S）-6，7-二甲氧基-3-（（R）-4-甲氧基-6-甲基-5，6，7，8-四氢[1，3]-二氧杂环戊烯-[4，5-g]异喹啉-5-基）异苯并呋喃-1（3 H）-酮（诺斯卡品）相比，对许多肿瘤细胞的IC 50低20倍。此外，EM 015对多种耐药细胞也有效。令人惊讶的是，非致瘤性正常细胞的细胞周期谱不受影响。今天临床上的许多抗微管癌症药物，特别是紫杉烷和紫杉醇，面临着挑战，包括频繁到医院进行长时间静脉输注，毒性和由于耐药性导致的肿瘤复发。另一方面，EM 015是口服的，在裸鼠模型中使乳腺肿瘤异种移植物消退，并延长寿命。此外，我们未能在组织中观察到任何可检测的毒性，例如肝、肾、脾、肺、心脏和脑以及神经元，其是抗微管药物治疗的常见靶点。因此，EM 015在临床上具有很大的前景。
We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, pi-pi, van der Waals, and hydrogen bonding interactions, to rationally design a new compound, EM015. This tubulin-binding semisynthetic compound is a selective and potent anti-breast cancer agent and displays a 20-fold lower IC50 against many tumor cells compared with our founding compound, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetraliydro[1,3]- dioxolo-[4,5-g]isoquinolin-5-yl)isobenzo-furan-1(3H)-one (noscapine). Furthermore, EM015 is also effective against a variety of drug-resistant cells. Surprisingly, the cell cycle profile of nontumorigenic normal cells is not affected. Many antimicrotubule cancer drugs in clinic today, particularly taxanes and Vincas, face challenges including frequent visits to the hospital for prolonged i.v. infusions, toxicities, and tumor recurrences due to drug resistance. EM015, on the other hand, is orally available, regresses breast tumor xenografts in nude mice models, and increases longevity. Furthermore, we have failed to observe any detectable toxicity in tissues, such as liver, kidney, spleen, lung, heart, and brain, as well as neurons, which are common targets of antimicrotubule drug therapy. Thus, EM015 has a great promise in the clinic.