A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity.
A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity.
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DOI：
10.1371/journal.pone.0045571
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Ling X;Cao S;Cheng Q;Keefe JT;Rustum YM;Li F
对治疗的药物/放射耐药性和肿瘤复发是确定治愈癌症的主要障碍。因此，开发解决这些挑战的新型药物在对抗癌症的斗争中至关重要。在这方面，研究表明抗凋亡蛋白survivin是参与这两个障碍的核心分子。利用基于癌细胞的生存素报告系统（US 7,569,221 B2），通过对化合物文库进行高通量筛选（HTS），然后对HTS衍生的hit-lead化合物进行体外和体内分析，我们鉴定出一种新的抗癌化合物（命名为FL118）。FL118与伊立替康结构相似。然而，虽然FL118对DNA拓扑异构酶1活性的抑制作用并不比伊立替康活性形式SN-38在1µM时更好，但FL118在小于nM水平下以p53状态无关的方式有效抑制癌细胞生长。此外，FL118也以p53状态无关的方式选择性地抑制survivin启动子活性和基因表达。虽然我们使用了survivin启动子报告系统来鉴定FL118，但我们的研究发现FL118不仅抑制survivin的表达，而且还以p53状态独立的方式选择性地独立抑制另外三个癌症相关存活基因（Mcl-1、XIAP和cIAP2），而对对照基因没有抑制作用。基因沉默或过表达FL118靶点表明这些靶点在FL118的作用中起作用。体内随访研究显示，与伊立替康、拓扑替康、阿霉素、5-FU、吉西他滨、多西他赛、奥沙利铂、环磷酰胺和顺铂相比，FL118在人类肿瘤异种移植模型中表现出更好的抗肿瘤效果，并且大多数接受FL118治疗的小鼠肿瘤以每周× 4的速度消退。FL118诱导了良好的体重减轻（暂时和可逆的），并能够消除大肿瘤。综上所述，FL118的分子靶向特性加上其优越的抗肿瘤活性保证了其进一步的临床试验开发。
Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 µM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118’s effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials.
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影响因子：
3.4
作者：
Hernandez JM;Farma JM;Coppola D;Hakam A;Fulp WJ;Chen DT;Siegel EM;Yeatman TJ;Shibata D
通讯作者：
Shibata D
DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
影响因子：
4.7
作者：
Barth, Stephan W.;Briviba, Karlis;Esselen, Melanie
通讯作者：
Esselen, Melanie
影响因子：
15.9
作者：
Dohi, T;Beltrami, E;Altieri, DC
通讯作者：
Altieri, DC
影响因子：
4.8
作者：
Dohi, T;Okada, K;Altieri, DC
通讯作者：
Altieri, DC