Abstract 4548: Identify novel molecular structures targeting X-Linked Inhibitor of Apoptosis Protein by ligand-based virtual screening.

Abstract

Abstract Resistance to apoptosis is believed as one of the mechanism underlying a number of human malignancies notorious resistances to current chemotherapeutics. The X-linked inhibitor of apoptosis protein (XIAP) inhibits apoptosis by directly binding and deactivating caspase-9, caspase-3/7. Elevated XIAP expression in tumor tissue is closely associated with metastatic progression. Mimicking the XIAP-binding motif of second mitochondria-derived activator of caspase (SMAC) is the most widely used strategy to discover or design therapeutic agents targeting XIAP. Here we screened a large database of 362K compounds (the University of Cincinnati's Drug Discovery Center Library) in silico to find molecules with novel structures that can strongly interact with the third BIR domain of XIAP. We chose AVPI tetrapeptide from the SMAC as the lead structure and run the shape similarity search using program Canvas, version 1.4 (Schrodinger, LLC, New York, USA). Then top 10,000 structures of the similarity rank were docked into SMAC binding sites in two different SMAC-BIR3 domain complexes crystal structure (PDB ID: 1TW1 and 1G73) separately. The highest docking score of the screened structures is up to -9.0 in both of complexes while the SMAC AVPI tetrapeptide showed docking score at -9.4. Considering the docking scores in both complexes and the flexibility of chemical scaffolds, we manually selected 72 compounds with docking scores varied from -8.4 to -5.5 for in vitro anti-proliferation and caspase functional testing. Four compounds which haven't been reported with any anti-cancer activity, inhibited the cell growth by over 70% in two human melanoma cell lines (A375 and MDA-MB-435) and two human prostate cell lines (PC-3 and LNCap) at the concentration of 10uM after 48hr incubation. IC50 values of those compounds were at least 4 folds smaller than that of Embelin, a well-recognized XIAP inhibitor, in all four cell lines tested. The best of them, compound 402112, have IC50 values of 650nM to 2.5uM against the four tested cancer cell lines. Caspase functional assay showed that compound 402112 activates capase-9 activity at 4 μM, significantly better than Embelin did at a 10-fold higher concentration (40 μM) after 48hr treatment in PC-3 and A375 cells. Taken together, our study identified novel molecule structures which are amicable to further extensive modification for the development of high potent XIAP inhibitors. Citation Format: Jin Wang, Charles B. Duke, Wei Li. Identify novel molecular structures targeting X-Linked Inhibitor of Apoptosis Protein by ligand-based virtual screening. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4548. doi:10.1158/1538-7445.AM2013-4548