Document Detail

Synthesis and Structure Activity Relationship Studies of Small Molecule Disruptors of EWS-FLI1 Interactions in Ewing Sarcoma.
MedLine Citation:
PMID:  25432018     Owner:  NLM     Status:  Publisher    
EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing sarcoma family tumors (ES). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues were measured by an EWS-FLI1/ NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control cell lines devoid of the protein (PANC1). Key structure activity relationships were identified and summarized. Further, a correlation of growth inhibition (EWS-FL1 expressing T32 cells) and the luciferase reporter activity was established (R(2) =0.92). Finally, we designed and synthesized a biotinylated analogue and assessed the binding affinity (Kd = 4.8 υM ± 2.6 υM) of the biotin containing analogue to recombinant EWS-FLI1.
Perrer N Tosso; Yali Kong; Lauren Scher; Ryan Cummings; Jeffrey Schneider; Said Rahim; Kevin Travis Holman; Jeffrey Toretsky; Kan Wang; Aykut Uren; Milton L Brown
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-28
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-28     Completed Date:  -     Revised Date:  2014-11-29    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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