A Novel Small Molecule FL118 That Selectively Inhibits Survivin, Mcl-1, XIAP and cIAP2 in a p53-Independent Manner, Shows Superior Antitumor Activity

Abstract

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.

Clinical aspects for survivin: a crucial molecule for targeting drug-resistant cancers

“…FL118 is capable of inhibiting survivin and other cancer survival genes and this inhibition is independent of the p53 status of the cells. FL118 showed superior antitumor activity when compared with a varying range of drugs such as cisplatin, doxorubicin, docetaxel, oxiplatin, among others, in mouse xenograft models [114].…”

FL118, a novel camptothecin analogue, suppressed migration and invasion of human breast cancer cells by inhibiting epithelial-mesenchymal transition <i>via</i> the Wnt/β-catenin signaling pathway

“…FL118 was found to display potent anticancer activity against several different types of cancer both in vitro and in vivo (17)(18)(19)(20). Moreover, its antitumor activity was superior to that of several camptothecin analogues, such as irinotecan and topotecan, that have been approved by the FDA for cancer treatment (21,22). FL118 is rapidly cleared from circulation and it effectively accumulates in tumors with a long half-life of elimination, suggesting its potential for use in cancer therapy (18,20).…”

Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy

“…FL118 [50] and GDP566 [51] are another two survivin selective inhibitors discovered by HTS that exhibit potent anti-tumor activity in vitro and in vivo. Since survivin inhibitors show only limited antitumor efficacy in clinical trials, it may be fruitful to combine these agents with conventional chemotherapeutic agents in future clinical trials [52].…”