title: 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.
authors.affiliation: Departments of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ling
authors.forename: Shousong
authors.initials: S
authors.lastname: Cao
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Cheng
authors.forename: James T
authors.initials: JT
authors.lastname: Keefe
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007212:Indolizines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C578515:7-ethyl-7-hydroxy-10H-1,3-Dioxolo(4,5-g)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-8,11(7H,12H)-dione; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D052117:Benzodioxoles; D007212:Indolizines; D051034:Inhibitor of Apoptosis Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D004264:DNA Topoisomerases, Type I