Abstract 4525: Discovery and characterization of a small chemical compound that shows exceptional antitumor activity and targets multiple antiapoptotic proteins in the inhibitor of apoptosis (IAP) and Bcl-2 families

Anticancer efficacy and selectivity are the two critical factors for successful cancer treatment. The classical approach for anticancer drug discovery is the use of cytotoxicity as a drug selection marker. The drug candidates discovered via this approach usually show little selectivity to cancer versus normal tissues. The modern cancer drug discovery and research focus on cancer-associated gene or pathway-targeted approaches. One challenging issue for targeted cancer therapy is that while monogene or mono-pathway-targeted drug shows little toxicity, it possesses minimal antitumor efficacy. On the other hand, targeting multiple cancer-associated genes or pathways via multiple drug combination usually results in over toxicity to normal tissues. One strategy to solve this challenging issue is to apply one drug targeting multiple cancer-associated genes and/or survival pathways. In this report, we describe the discovery and characterization of a clinical favorable small chemical compound that targets multiple antiapoptotic proteins in the inhibitor of apoptosis (IAP) and Bcl-2 families. Using a high throughput screening (HTS) system (US Patent 7569221, 2009), we screened several small chemical compound libraries from various sources, followed by in vitro and in vivo analyses of HTS-derived hits-relevant analogs. The efforts finally resulted in an exceptional antitumor compound designated FL118. Although compound libraries were initially screened using the survivin gene as a target and biomarker, FL118 was found to selectively inhibit the expression of survivin, XIAP, c-IAP2 and Mcl-2, while it shows no inhibitory effects on promoter activity for the genes of p21WAF1/CIP1, DHFR, human thrombin receptor and TK. In addition, FL118 inhibited Akt activation, while showing no inhibitory effects on Erk1/2 activation. FL118 showed superior antitumor activity in human tumor animal models in comparison with other FDA-approved anticancer drugs including irinotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan, cisplatin and topotecan. Although the FL118 compound structurally has similarity to irinotecan, FL118 is a poor topoisomerase I (Top1) inhibitor in comparison with the active form of irinotecan (a known Top1 inhibitor), SN-38. Using the best schedule (weeklyx4) for irinotecan in a human head-&-neck tumor xenograft mouse model, we showed that while 40% mice treated with irinotecan show a temporary cure with rapid relapse, 100% mice treated with FL118 show permanent cure without relapse. Furthermore, FL118 effectively cures large and late stage tumors in animal models. These innovative properties for FL118 lay a foundation for its further development as an exceptional drug for effective cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4525. doi:10.1158/1538-7445.AM2011-4525