FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2313223468> ?p ?o ?g. }

• W2313223468 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 Cincinnati9s 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 haven9t 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" @default.
• W2313223468 created "2016-06-24" @default.
• W2313223468 creator A5000432967 @default.
• W2313223468 creator A5017977887 @default.
• W2313223468 creator A5018244700 @default.
• W2313223468 date "2013-04-15" @default.
• W2313223468 modified "2023-09-22" @default.
• W2313223468 title "Abstract 4548: Identify novel molecular structures targeting X-Linked Inhibitor of Apoptosis Protein by ligand-based virtual screening." @default.
• W2313223468 doi "https://doi.org/10.1158/1538-7445.am2013-4548" @default.
• W2313223468 hasPublicationYear "2013" @default.
• W2313223468 type Work @default.
• W2313223468 sameAs 2313223468 @default.
• W2313223468 citedByCount "0" @default.
• W2313223468 crossrefType "proceedings-article" @default.
• W2313223468 hasAuthorship W2313223468A5000432967 @default.
• W2313223468 hasAuthorship W2313223468A5017977887 @default.
• W2313223468 hasAuthorship W2313223468A5018244700 @default.
• W2313223468 hasConcept C103697762 @default.
• W2313223468 hasConcept C104317684 @default.
• W2313223468 hasConcept C12519072 @default.
• W2313223468 hasConcept C159110408 @default.
• W2313223468 hasConcept C170493617 @default.
• W2313223468 hasConcept C185592680 @default.
• W2313223468 hasConcept C190283241 @default.
• W2313223468 hasConcept C207001950 @default.
• W2313223468 hasConcept C2775905019 @default.
• W2313223468 hasConcept C2776055636 @default.
• W2313223468 hasConcept C2777408456 @default.
• W2313223468 hasConcept C2779281246 @default.
• W2313223468 hasConcept C2779564779 @default.
• W2313223468 hasConcept C31573885 @default.
• W2313223468 hasConcept C33195913 @default.
• W2313223468 hasConcept C41685203 @default.
• W2313223468 hasConcept C502942594 @default.
• W2313223468 hasConcept C54355233 @default.
• W2313223468 hasConcept C55493867 @default.
• W2313223468 hasConcept C56173144 @default.
• W2313223468 hasConcept C65556437 @default.
• W2313223468 hasConcept C70721500 @default.
• W2313223468 hasConcept C71924100 @default.
• W2313223468 hasConcept C86803240 @default.
• W2313223468 hasConcept C88045685 @default.
• W2313223468 hasConcept C98424977 @default.
• W2313223468 hasConceptScore W2313223468C103697762 @default.
• W2313223468 hasConceptScore W2313223468C104317684 @default.
• W2313223468 hasConceptScore W2313223468C12519072 @default.
• W2313223468 hasConceptScore W2313223468C159110408 @default.
• W2313223468 hasConceptScore W2313223468C170493617 @default.
• W2313223468 hasConceptScore W2313223468C185592680 @default.
• W2313223468 hasConceptScore W2313223468C190283241 @default.
• W2313223468 hasConceptScore W2313223468C207001950 @default.
• W2313223468 hasConceptScore W2313223468C2775905019 @default.
• W2313223468 hasConceptScore W2313223468C2776055636 @default.
• W2313223468 hasConceptScore W2313223468C2777408456 @default.
• W2313223468 hasConceptScore W2313223468C2779281246 @default.
• W2313223468 hasConceptScore W2313223468C2779564779 @default.
• W2313223468 hasConceptScore W2313223468C31573885 @default.
• W2313223468 hasConceptScore W2313223468C33195913 @default.
• W2313223468 hasConceptScore W2313223468C41685203 @default.
• W2313223468 hasConceptScore W2313223468C502942594 @default.
• W2313223468 hasConceptScore W2313223468C54355233 @default.
• W2313223468 hasConceptScore W2313223468C55493867 @default.
• W2313223468 hasConceptScore W2313223468C56173144 @default.
• W2313223468 hasConceptScore W2313223468C65556437 @default.
• W2313223468 hasConceptScore W2313223468C70721500 @default.
• W2313223468 hasConceptScore W2313223468C71924100 @default.
• W2313223468 hasConceptScore W2313223468C86803240 @default.
• W2313223468 hasConceptScore W2313223468C88045685 @default.
• W2313223468 hasConceptScore W2313223468C98424977 @default.
• W2313223468 hasLocation W23132234681 @default.
• W2313223468 hasOpenAccess W2313223468 @default.
• W2313223468 hasPrimaryLocation W23132234681 @default.
• W2313223468 hasRelatedWork W1011422075 @default.
• W2313223468 hasRelatedWork W1940268772 @default.
• W2313223468 hasRelatedWork W1971236569 @default.
• W2313223468 hasRelatedWork W1976353819 @default.
• W2313223468 hasRelatedWork W1999546013 @default.
• W2313223468 hasRelatedWork W2040370168 @default.
• W2313223468 hasRelatedWork W2049464805 @default.
• W2313223468 hasRelatedWork W2076721909 @default.
• W2313223468 hasRelatedWork W2093556522 @default.
• W2313223468 hasRelatedWork W2108177656 @default.
• W2313223468 hasRelatedWork W2192728310 @default.
• W2313223468 hasRelatedWork W2245158538 @default.
• W2313223468 hasRelatedWork W2330849330 @default.
• W2313223468 hasRelatedWork W2519582051 @default.
• W2313223468 hasRelatedWork W2556996985 @default.
• W2313223468 hasRelatedWork W2801556832 @default.
• W2313223468 hasRelatedWork W3015847972 @default.
• W2313223468 hasRelatedWork W3080199553 @default.
• W2313223468 hasRelatedWork W42960221 @default.
• W2313223468 hasRelatedWork W595813438 @default.
• W2313223468 isParatext "false" @default.
• W2313223468 isRetracted "false" @default.
• W2313223468 magId "2313223468" @default.
• W2313223468 workType "article" @default.