Journal
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
Volume 9, Issue 4, Pages 437-456Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1871520610909040437
Keywords
Apoptosis inducers; HTS assay; anti-cancer drug; SAR studies; tubulin inhibitors; vascular disrupting agent (VDA)
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Many cancer cells are known to have defects in the apoptosis machinery. Therefore identification of compounds that can activate or promote apoptosis in cancer cells is an attractive approach for targeted therapies. By applying a novel cell- and caspase-based Anti-cancer Screening Apoptosis Program (ASAP) HTS assay, 4-aryl-4H-chromenes were identified as potent apoptosis inducers. 4-Aryl-4H-chromenes were found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G(2)/M stage followed by apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e. g. Jurkat, T47D). These compounds were found to be highly active in the growth inhibition MTT assay, including for paclitaxel resistant, p-glycoprotein overexpressed, MES-SA/DX5 tumor cells. Functionally, they were found to be potent inhibitors of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. In addition, several 4-aryl-4H-chromenes were also found to be effective vascular disrupting agents (VDA). One of the lead compounds, EPC2407, is currently in clinical trials as a novel tumor vascular disrupting agent.
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