a novel small molecule fl118 that selectively inhibits survivin, mcl-1, xiap and ciap2 in a p53-independent manner, shows superior antitumor activity一种新型小分子fl118选择性地抑制存活素,mcl1,xiap和ciap2 p53-independent方式,显示了优越的抗肿瘤活性.pdfVIP

A Novel Small Molecule FL118 That Selectively Inhibits Survivin, Mcl-1, XIAP and cIAP2 in a p53-Independent Manner, Shows Superior Antitumor Activity 1. 1,2. 1 1 1,3 1,3 Xiang Ling , Shousong Cao , Qiuying Cheng , James T. Keefe , Youcef M. Rustum , Fengzhi Li * 1 Departments of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, United States of America, 2 Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, United States of America, 3 NCI-supported Experimental Therapeutics Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America 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 mM, 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-